Heterocyclic compound

ABSTRACT

The present invention aims to provide a compound that may be useful for the prophylaxis or treatment of constipation and the like. The present invention provides a compound represented by the following formula (I): 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as described in the specification, or a salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.16/622,632, which is the the U.S. National Stage of PCT/JP2018/023357,filed Jun. 19, 2018, which claims priority from U.S. ProvisionalApplication No. 62/683,418, filed Jun. 11, 2018, JP 2017-120859, filedJun. 20, 2017, and JP 2018-005960, filed Jan. 17, 2018.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound possibly havinga cholinergic muscarinic M1 receptor positive allosteric modulatoractivity and possibly useful as a medicament such as a prophylactic ortherapeutic drug for constipation and the like. As used herein, thepositive allosteric modulator activity refers to an action to potentiatereceptor function by binding to a moiety different from that of anendogenous activator (acetylcholine for this receptor).

BACKGROUND OF THE INVENTION

Acetylcholine is a neurotransmitter that induces signal transduction inthe central nervous system and the neuromuscular connections (theparasympathetic nerve and motor nerve). In the gastrointestinal tract,myenteric plexus, submucosal plexus and the like form a neural networkand control gastrointestinal function. Of these, acetylcholine is amajor neurotransmitter in the gastrointestinal function and plays a keyrole in the gastrointestinal motility.

Acetylcholine receptor is classified into a ligand dependent ion channel(cholinergic nicotinic receptor) and a G-protein-conjugated receptor(cholinergic muscarinic receptor). The cholinergic muscarinic receptoris one kind of receptor for excitatory neurotransmitter acetylcholine,and was named based on the selective activation of the receptor bymuscarine. The muscarinic receptor is further classified into subtypesof M1 to M5, and the M1 receptor is known to be widely distributedmainly in the brain. On the other hand, expression of M1 receptor in thegastrointestinal nerve plexus is also known and its role of regulatingthe functions of the gastrointestinal tract has been pointed out(non-patent document 1). From the studies in recent years, promotion ofgastrointestinal motility by cholinergic M1 receptor agonist has alsobeen reported.

Generally, peristalsis in the gastrointestinal tract consists ofcoordinated contraction and relaxation at adjacent sites. It is alsoknown that the cholinergic M1 receptor is expressed in both theexcitatory nerve and inhibitory nerve in the gastrointestinal nerveplexus (non-patent document 1).

WO2013/129622 (patent document 1) discloses the following compoundhaving a cholinergic muscarinic M1 receptor positive allostericmodulator (M1PAM) activity and useful for the treatment of Alzheimer'sdisease, schizophrenia, pain, sleep disorder and the like.

wherein each symbol is as defined in the document.

WO2014/077401 (patent document 2) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer'sdisease, schizophrenia, pain, sleep disorder and the like.

wherein each symbol is as defined in the document.

WO2015/174534 (patent document 3) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer'sdisease, schizophrenia, pain, sleep disorder, Parkinson's diseasedementia, Lewy body dementia and the like.

wherein each symbol is as defined in the document.

WO2015/163485 (patent document 4) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer'sdisease, schizophrenia, pain, sleep disorder, Parkinson's diseasedementia, Lewy body dementia and the like.

wherein each symbol is as defined in the document.

WO2016/208775 (patent document 5) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer'sdisease, schizophrenia, pain, sleep disorder, Parkinson's diseasedementia, Lewy body dementia and the like.

wherein each symbol is as defined in the document.

WO2015/190564 (patent document 6) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer'sdisease, schizophrenia, pain, sleep disorder, Parkinson's diseasedementia, Lewy body dementia and the like.

wherein each symbol is as defined in the document.

DOCUMENT LIST Patent Documents

-   patent document 1: WO2013/129622-   patent document 2: WO2014/077401-   patent document 3: WO2015/174534-   patent document 4: WO2015/163485-   patent document 5: WO2016/208775-   patent document 6: WO2015/190564

Non-Patent Document

-   non-patent document 1: Journal of Chemical Neuroanatomy, 2007 July,    33(4), 193-201

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The development of a compound having a cholinergic muscarine M1 receptor(M1 receptor) positive allosteric modulator activity and useful as aprophylactic or therapeutic agent for constipation, for example,constipation associated with neurological disease (e.g., Parkinson'sdisease, spinal cord injury, multiple sclerosis), idiopathicconstipation, age-related constipation, opioid-induced constipation andthe like is desired. As used herein, the positive allosteric modulatoractivity means an action to bind to a site different from an endogenousactivator (acetylcholine in this receptor) and potentiate the receptorfunction.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the aforementioned problems and found that a compound representedby the following formula (I) may have a cholinergic muscarinic M1receptor positive allosteric modulator activity, which resulted in thecompletion of the present invention.

Therefore, the present invention relates to the following.

[1] A compound represented by the formula (I):

wherein

R¹ is an optionally substituted cyclic group;

R² is a hydrogen atom, a halogen atom, a cyano group, an optionallysubstituted C₁₋₆ alkyl group, or an optionally substituted C₁₋₆ alkoxygroup;

is a single bond or a double bond;

ring A is an optionally further substituted ring; and

R³ and R⁴ are each independently a hydrogen atom, a halogen atom, ahydroxy group, an optionally substituted C₁₋₆ alkyl group, or anoptionally substituted C₁₋₆ alkoxy group, or a salt thereof (sometimesto be abbreviated as “compound (I)” in the present specification).

[2] The compound described in the above-mentioned [1], wherein

R¹ is

(1) an optionally substituted 3- to 14-membered non-aromaticheterocyclic group, or

(2) an optionally substituted C₃₋₁₀ cycloalkyl group;

R² is a hydrogen atom or an optionally substituted C₁₋₆ alkyl group;ring A is

(1) an optionally further substituted benzene ring,

(2) an optionally further substituted 5- or 6-membered monocyclicaromatic heterocycle,

(3) an optionally further substituted 4- to 6-membered monocyclicnon-aromatic heterocycle, or

(4) an optionally further substituted 9- to 14-membered fused polycyclicnon-aromatic heterocycle; and

R³ and R⁴ are each independently a hydrogen atom, a halogen atom or anoptionally substituted C₁₋₆ alkyl group, or a salt thereof.[3] The compound described in the above-mentioned [1], wherein

R¹ is

(1) a 3- to 14-membered non-aromatic heterocyclic group optionallysubstituted by 1 to 3 hydroxy groups, or

(2) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3substituents selected from a hydroxy group and a halogen atom;

R² is a hydrogen atom or a C₁₋₆ alkyl group;ring A is

(1) a benzene ring optionally further substituted by 1 to 3 substituentsselected from (a) a halogen atom, (b) a C₁₋₆ alkoxy group, (c) a mono-or di-C₁₋₆ alkyl-carbamoyl group optionally substituted by 1 or 2substituents selected from (i) a C₁₋₆ alkoxy group, (ii) a C₃₋₁₀cycloalkyl group, (iii) a 3- to 14-membered non-aromatic heterocyclicgroup, (iv) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 hydroxygroups, (v) a C₁₋₆ alkoxy-carbonyl group, (vi) a carboxy group, (vii) aC₁₋₆ alkylthio group, (viii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,and (ix) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(d) a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group, (e) a C₆₋₁₄aryl-carbamoyl group optionally substituted by 1 to 3 hydroxy groups,and (f) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups,

(2) a 5- or 6-membered monocyclic aromatic heterocycle optionallyfurther substituted by 1 to 3 substituents selected from (a) a C₁₋₆alkoxy group and (b) a 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups,

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle optionallyfurther substituted by one oxo group, or

(4) a 9- to 14-membered fused polycyclic non-aromatic heterocycleoptionally further substituted by 1 to 3 substituents selected from aC₁₋₆ alkyl group and an oxo group; and

R³ and R⁴ are each independently a hydrogen atom, a halogen atom or aC₁₋₆ alkyl group, or a salt thereof.[4] The compound described in the above-mentioned [3], wherein

R¹ is

or a salt thereof.[5] The compound described in the above-mentioned [3], wherein ring A is

(1) a benzene ring further substituted by 1 to 3 substituents selectedfrom (a) a halogen atom, (b) a mono- or di-C₁₋₆ alkyl-carbamoyl groupoptionally substituted by 1 or 2 substituents selected from (i) a C₁₋₆alkoxy group and (ii) a 3- to 14-membered non-aromatic heterocyclicgroup, and (c) a 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups, or

(2) a 5- or 6-membered monocyclic aromatic heterocycle furthersubstituted by one 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups, or a salt thereof.

[6] The compound described in the above-mentioned [3], wherein ring A is

wherein R^(5A) is a mono- or di-C₁₋₆ alkyl-carbamoyl group optionallysubstituted by 1 or 2 substituents selected from a C₁₋₆ alkoxy group anda 3- to 14-membered non-aromatic heterocyclic group;

X is CR^(6A) or N; and

R^(6A) is a hydrogen atom or a halogen atom, or a salt thereof.[7] The compound described in the above-mentioned [3], wherein ring A is

wherein R^(5A) is a 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups;

X is CR^(6A) or N; and

R^(6A) is a hydrogen atom or a halogen atom,or a salt thereof.[8] The compound described in the above-mentioned [1], wherein R¹ is a3- to 14-membered non-aromatic heterocyclic group substituted by onehydroxy group;R² is a hydrogen atom;ring A is

(1) a benzene ring further substituted by 1 to 3 substituents selectedfrom (a) a halogen atom, (b) a mono- or di-C₁₋₆ alkyl-carbamoyl groupoptionally substituted by 1 or 2 substituents selected from (i) a C₁₋₆alkoxy group and (ii) a 3- to 14-membered non-aromatic heterocyclicgroup, and (c) a 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups, or

(2) a 5- or 6-membered monocyclic aromatic heterocycle furthersubstituted by one 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups; and

R³ and R⁴ are each independently a hydrogen atom or a halogen atom,or a salt thereof.[9]N-((3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxamide,or a salt thereof.[10]N-((3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide,or a salt thereof.[11]7-(3-Fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide,or a salt thereof.[12]7-(3-Fluoro-4-((((S)-tetrahydrofuran-2-yl)methyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide,or a salt thereof.[13]7-(3-Fluoro-4-((((S)-tetrahydrofuran-2-yl)methyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)furo[3,2-b]pyridine-5-carboxamide,or a salt thereof.[14] A medicament comprising the compound described in theabove-mentioned [1] or a salt thereof.[15] The medicament described in the above-mentioned [14], which is acholinergic muscarinic M1 receptor positive allosteric modulator.[16] The medicament described in the above-mentioned [14], which is aprophylactic or therapeutic agent for constipation.[17] A method of cholinergic muscarinic M1 receptor positive allostericmodulation in a mammal, comprising administering an effective amount ofthe compound described in the above-mentioned [1] or a salt thereof tosaid mammal.[18] A method for the prophylaxis or treatment of constipation in amammal, comprising administering an effective amount of the compounddescribed in the above-mentioned [1] or a salt thereof to the mammal.[19] Use of the compound described in the above-mentioned [1] or a saltthereof in the production of a prophylactic or therapeutic agent forconstipation.[20] The compound described in the above-mentioned [1] or a salt thereoffor use in the prophylaxis or treatment of constipation.

Effect of the Invention

The compound of the present invention may have a cholinergic muscarinicM1 receptor positive allosteric modulator activity, and may be useful asa medicament such as a prophylactic or therapeutic drug for, forexample, constipation, such as constipation associated with neurologicaldisease (e.g., Parkinson's disease, spinal cord injury, multiplesclerosis), idiopathic constipation, age-related constipation,opioid-induced constipation and the like.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl. In the present specification,examples of the “optionally halogenated C₃₋₁₀ cycloalkyl group” includea C₃₋₁₀ cycloalkyl group optionally having 1 to 7, preferably 1 to 5,halogen atoms. Specific examples thereof include cyclopropyl,2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl,difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₄ aryl-carbonyl group”include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[substituent group A](1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group and (62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a(C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁-6 alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “hydrocarbocycle” includea C₆₋₁₄ aromatic hydrocarbocycle, C₃₋₁₀ cycloalkane and C₃₋₁₀cycloalkene.

In the present specification, examples of the “C₆-14 aromatichydrocarbocycle” include benzene and naphthalene.

In the present specification, examples of the “C₃₋₁₀ cycloalkane”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene.

In the present specification, examples of the “heterocyclic group”include an aromatic heterocyclic group and a non-aromatic heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” include a 5- to 14-membered (preferably 5- to 10-membered)aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom. Preferable examples of the “aromaticheterocycle” include 5- or 6-membered monocyclic aromatic heterocyclessuch as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole,isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine,pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and 8- to14-membered fused polycycle (preferably bi or tricyclic) aromaticheterocycles such as benzothiophene, benzofuran, benzimidazole,benzoxazole, benzisoxazole, benzothiazole, benzisothiazole,benzotriazole, imidazopyridine, thienopyridine, furopyridine,pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine,imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine,pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine,thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine,naphtho[2,3-b]thiophene, phenoxathiine, indole, isoindole, 1H-indazole,purine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, carbazole, β-carboline,phenanthridine, acridine, phenazine, phenothiazine, phenoxathiine andthe like.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocyclic groupssuch as aziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, Pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepanine, diazepane, azepine, azocane, diazocane, oxepane and the like;and 9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzoimidazole, dihydrobenzooxazole, dihydrobenzothiazole,dihydrobenzoisothiazole, dihydronaphto[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzoazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include the “heterocycle” containing at least one nitrogenatom as a ring-constituting atom.

Each symbol in the formula (I) is explained below.

R¹ is an optionally substituted cyclic group.

As the “optionally substituted cyclic group” for R¹, an optionallysubstituted heterocyclic group, and an optionally substitutednon-aromatic hydrocarbon ring group can be mentioned.

As the “heterocyclic group” of the “optionally substituted heterocyclicgroup” for R¹, a 3- to 14-membered non-aromatic heterocyclic group(e.g., tetrahydropyranyl) is preferable. As the substituent, 1 to 3(preferably 1) hydroxy groups are preferable.

As the “non-aromatic hydrocarbon ring group” of the “optionallysubstituted non-aromatic hydrocarbon ring group” for R¹, a C₃₋₁₀cycloalkyl group (e.g., cyclobutyl, cyclopentyl, cyclohexyl) ispreferable. As the substituent, 1 to 3 (preferably 1) substituentsselected from a hydroxy group and a halogen atom (e.g., fluorine atom)are preferable.

R¹ is preferably

(1) an optionally substituted 3- to 14-membered non-aromaticheterocyclic group, or(2) an optionally substituted C₃₋₁₀ cycloalkyl group.

R¹ is more preferably

(1) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 (preferably 1)hydroxy groups, or(2) a C₃₋₁₀ cycloalkyl group (e.g., cyclobutyl, cyclopentyl, cyclohexyl)optionally substituted by 1 to 3 (preferably 1) substituents selectedfrom a hydroxy group and a halogen atom (e.g., fluorine atom).

R¹ is further preferably

(1) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) substituted by one hydroxy group, or(2) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) substituted by 1 to 3(preferably 1) substituents selected from a hydroxy group and a halogenatom (e.g., fluorine atom).

R¹ is furthermore preferably a 3- to 14-membered non-aromaticheterocyclic group (e.g., tetrahydropyranyl) substituted by one hydroxygroup.

In another embodiment of the present invention, R¹ is preferably

more preferably,

further preferably,

particularly preferably,

In another embodiment of the present invention, R¹ is preferably

more preferably,

further preferably,

furthermore preferably,

particularly preferably,

R² is a hydrogen atom, a halogen atom, a cyano group, an optionallysubstituted C₁₋₆ alkyl group, or an optionally substituted C₁₋₆ alkoxygroup.

R² is preferably a hydrogen atom, a halogen atom (e.g., chlorine atom,fluorine atom), a C₁₋₆ alkyl group (e.g., methyl), or a C₁₋₆ alkoxygroup (e.g., methoxy), more preferably, a hydrogen atom or a C₁₋₆ alkylgroup (e.g., methyl), further preferably, a hydrogen atom.

is a single bond or a double bond.

In one embodiment of the present invention,

is a single bond.

In another embodiment of the present invention,

is a double bond.

Ring A is an optionally further substituted ring.

As the “optionally further substituted ring” for ring A, an optionallyfurther substituted 4- to 6-membered monocyclic hydrocarbon ring, anoptionally further substituted 5- or 6-membered monocyclic aromaticheterocycle, an optionally further substituted 4- to 6-memberedmonocyclic non-aromatic heterocycle, and an optionally furthersubstituted 9- to 14-membered fused polycyclic (preferably bicyclic ortricyclic) non-aromatic heterocycle can be mentioned.

As the “4- to 6-membered monocyclic hydrocarbon ring” of the “optionallyfurther substituted 4- to 6-membered monocyclic hydrocarbon ring” forring A, a benzene ring, a C₄₋₆ cycloalkane ring (e.g., cyclobutane ring,cyclopentane ring, cyclohexane ring), and a C₄₋₆ cycloalkene ring (e.g.,cyclobutene ring, cyclopentene ring, cyclohexene ring) can be mentioned.As the “4- to 6-membered monocyclic hydrocarbon ring”, a benzene ringcan be preferably mentioned.

As the substituent of the “optionally further substituted 4- to6-membered monocyclic hydrocarbon ring” for ring A, 1 to 3 substituentsselected from (1) a cyano group, (2) a halogen atom, (3) a carboxygroup, (4) an optionally substituted hydroxy group, (5) an optionallysubstituted carbamoyl group, (6) an optionally substituted amino group,(7) an optionally substituted heterocyclic group and (8) an optionallysubstituted hydrocarbon group can be mentioned.

As the “5- or 6-membered monocyclic aromatic heterocycle” of the“optionally further substituted 5- or 6-membered monocyclic aromaticheterocycle” for ring A, a 5- or 6-membered monocyclic aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom (e.g., thiophene ring, furan ring, pyrrole ring, imidazolering, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring,isoxazole ring, pyridine ring, pyrazine ring, pyrimidine ring,pyridazine ring, 1,2,4-oxadiazole ring, 1,3,4-oxadiazole ring,1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, triazole ring, tetrazolering, triazine ring) can be mentioned. As the “5- or 6-memberedmonocyclic aromatic heterocycle”, pyridine ring can be preferablymentioned.

As the substituent of the “optionally further substituted 5- or6-membered monocyclic aromatic heterocycle” for ring A, 1 to 3substituents selected from (1) a cyano group, (2) a halogen atom, (3) acarboxy group, (4) an optionally substituted hydroxy group, (5) anoptionally substituted carbamoyl group, (6) an optionally substitutedamino group, (7) an optionally substituted heterocyclic group and (8) anoptionally substituted hydrocarbon group can be mentioned.

As the “4- to 6-membered monocyclic non-aromatic heterocycle” of the“optionally further substituted 4- to 6-membered monocyclic non-aromaticheterocycle” for ring A, a 4- to 6-membered monocyclic non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom (e.g., azetidine ring, oxetane ring, thietane ring,tetrahydrothiophene ring, tetrahydrofuran ring, pyrroline ring,pyrrolidine ring, imidazoline ring, imidazolidine ring, oxazoline ring,oxazolidine ring, pyrazoline ring, pyrazolidine ring, thiazoline ring,thiazolidine ring, tetrahydroisothiazole ring, tetrahydroisoxazole ring,piperidine ring, piperazine ring, tetrahydropyridine ring,dihydropyridine ring, dihydrothiopyran ring, tetrahydropyrimidine ring,tetrahydropyridazine ring, dihydropyran ring, tetrahydropyran ring,tetrahydrothiopyran ring, morpholine ring, thiomorpholine ring) can bementioned. As the “4- to 6-membered monocyclic non-aromaticheterocycle”, dihydropyridine ring can be preferably mentioned.

As the substituent of the “optionally further substituted 4- to6-membered monocyclic non-aromatic heterocycle” for ring A, 1 to 3substituents selected from (1) a cyano group, (2) a halogen atom, (3) acarboxy group, (4) an optionally substituted hydroxy group, (5) anoptionally substituted carbamoyl group, (6) an optionally substitutedamino group, (7) an optionally substituted heterocyclic group, (8)optionally substituted hydrocarbon group and (9) an oxo group can bementioned.

As the “9- to 14-membered fused polycyclic (preferably bicyclic ortricyclic) non-aromatic heterocycle” of the “optionally furthersubstituted 9- to 14-membered fused polycyclic (preferably bicyclic ortricyclic) non-aromatic heterocycle” for ring A, a 9- to 14-memberedfused polycyclic (preferably bicyclic or tricyclic) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom (e.g., dihydrobenzofuran ring, dihydrobenzimidazole ring,dihydrobenzoxazole ring, dihydrobenzothiazole ring,dihydrobenzisothiazole ring, dihydronaphtho[2,3-b]thiophene ring,tetrahydroisoquinoline ring, tetrahydroquinoline ring, 4H-quinolizinering, indoline ring, isoindoline ring, tetrahydrothieno[2,3-c]pyridinering, tetrahydrobenzazepine ring, tetrahydroquinoxaline ring,tetrahydrophenanthridine ring, hexahydrophenothiazine ring,hexahydrophenoxazine ring, tetrahydrophthalazine ring,tetrahydronaphthyridine ring, tetrahydroquinazoline ring,tetrahydrocinnoline ring, tetrahydrocarbazole ring,tetrahydro-β-carboline ring, tetrahydroacridine ring,tetrahydrophenazine ring, tetrahydrothioxanthene ring,octahydroisoquinoline ring) can be mentioned. As the “9- to 14-memberedfused polycyclic (preferably bicyclic or tricyclic) non-aromaticheterocycle”, isoindoline ring can be preferably mentioned.

As the substituent of the “optionally further substituted 9- to14-membered fused polycyclic (preferably bicyclic or tricyclic)non-aromatic heterocycle” for ring A, 1 to 3 substituents selected from(1) a cyano group, (2) a halogen atom, (3) a carboxy group, (4) anoptionally substituted hydroxy group, (5) an optionally substitutedcarbamoyl group, (6) an optionally substituted amino group, (7) anoptionally substituted heterocyclic group, (8) an optionally substitutedhydrocarbon group and (9) an oxo group can be mentioned.

As the “optionally substituted hydroxy group” which is a substituent ofthe “optionally further substituted 4- to 6-membered monocyclichydrocarbon ring”, the “optionally further substituted 5- or 6-memberedmonocyclic aromatic heterocycle”, the “optionally further substituted 4-to 6-membered monocyclic non-aromatic heterocycle” or the “optionallyfurther substituted 9- to 14-membered fused polycyclic (preferablybicyclic or tricyclic) non-aromatic heterocycle” for ring A, a C₁₋₆alkoxy group is preferable.

As the “optionally substituted carbamoyl group” which is a substituentof the “optionally further substituted 4- to 6-membered monocyclichydrocarbon ring”, the “optionally further substituted 5- or 6-memberedmonocyclic aromatic heterocycle”, the “optionally further substituted 4-to 6-membered monocyclic non-aromatic heterocycle” or the “optionallyfurther substituted 9- to 14-membered fused polycyclic (preferablybicyclic or tricyclic) non-aromatic heterocycle” for ring A, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₃₋₁₀ cycloalkyl-carbamoylgroup, or a C₆₋₁₄ aryl-carbamoyl group, each of which is optionallysubstituted is preferable.

As the “optionally substituted heterocyclic group” which is asubstituent of the “optionally further substituted 4- to 6-memberedmonocyclic hydrocarbon ring”, the “optionally further substituted 5- or6-membered monocyclic aromatic heterocycle”, the “optionally furthersubstituted 4- to 6-membered monocyclic non-aromatic heterocycle” or the“optionally further substituted 9- to 14-membered fused polycyclic(preferably bicyclic or tricyclic) non-aromatic heterocycle” for ring A,a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups is preferable.

Ring A is preferably

(1) an optionally further substituted benzene ring,(2) an optionally further substituted 5- or 6-membered monocyclicaromatic heterocycle,(3) an optionally further substituted 4- to 6-membered monocyclicnon-aromatic heterocycle, or(4) an optionally further substituted 9- to 14-membered fused polycyclicnon-aromatic heterocycle.

Ring A is more preferably

(1) a benzene ring optionally further substituted by 1 to 3 (preferably1 or 2, more preferably 1) substituents selected from

(a) a halogen atom (e.g., fluorine atom),

(b) a C₁₋₆ alkoxy group (e.g., methoxy),

(c) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,isobutylcarbamoyl, pentylcarbamoyl) optionally substituted by 1 or 2(preferably 1) substituents selected from

(i) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, tert-butoxy),

(ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclopentyl),

(iii) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydrofuranyl, tetrahydropyranyl),

(iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3(preferably 1) hydroxy groups,

(v) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl),

(vi) a carboxy group,

(vii) a C₁₋₆ alkylthio group (e.g., isopropylthio, tert-butylthio),

(viii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,dimethylcarbamoyl, diethylcarbamoyl), and

(ix) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group (e.g.,pyrrolidin-1-ylcarbonyl),

(d) a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl),

(e) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl) optionallysubstituted by 1 to 3 (preferably 1) hydroxy groups, and

(f) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionallysubstituted by 1 to 3 (preferably 1 or 2, more preferably 1) C₁₋₆ alkylgroups (e.g., methyl),

(2) a 5- or 6-membered monocyclic aromatic heterocycle (e.g., pyridinering) optionally further substituted by 1 to 3 (preferably 1 or 2, morepreferably 1) substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,triazolyl) optionally substituted by 1 to 3 (preferably 1 or 2, morepreferably 1) C₁₋₆ alkyl groups (e.g., methyl),

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle (e.g.,dihydropyridine ring) optionally further substituted by one oxo group,or(4) a 9- to 14-membered fused polycyclic (preferably bicyclic ortricyclic) non-aromatic heterocycle (e.g., isoindoline ring) optionallyfurther substituted by 1 to 3 (preferably 1 or 2) substituents selectedfrom a C₁₋₆ alkyl group (e.g., methyl) and an oxo group.

Ring A is further preferably

(1) a benzene ring optionally further substituted by 1 to 3 (preferably1 or 2, more preferably 1) substituents selected from

(a) a halogen atom (e.g., fluorine atom),

(b) a C₁₋₆ alkoxy group (e.g., methoxy),

(c) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl) optionally substituted by 1 or 2 (preferably 1)substituents selected from

(i) a C₁₋₆ alkoxy group (e.g., methoxy), and

(ii) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydrofuranyl), and

(d) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionallysubstituted by 1 to 3 (preferably 1 or 2, more preferably 1) C₁₋₆ alkylgroups (e.g., methyl),

(2) a 5- or 6-membered monocyclic aromatic heterocycle (e.g., pyridinering) optionally further substituted by 1 to 3 (preferably 1 or 2, morepreferably 1) substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,triazolyl) optionally substituted by 1 to 3 (preferably 1 or 2, morepreferably 1) C₁₋₆ alkyl groups (e.g., methyl), or

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle (e.g.,dihydropyridine ring) optionally further substituted by one oxo group.

Ring A is furthermore preferably

(1) a benzene ring further substituted by 1 to 3 (preferably 1 or 2)substituents selected from

(a) a halogen atom (e.g., fluorine atom),

(b) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl) optionally substituted by 1 or 2 (preferably 1)substituents selected from

(i) a C₁₋₆ alkoxy group (e.g., methoxy), and

(ii) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydrofuranyl), and

(c) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl, preferably,pyrazolyl, triazolyl, imidazolyl) optionally substituted by 1 to 3(preferably 1 or 2, more preferably 1) C₁₋₆ alkyl groups (e.g., methyl),or

(2) a 5- or 6-membered monocyclic aromatic heterocycle (e.g., pyridinering) further substituted by one 5- to 14-membered aromatic heterocyclicgroup (e.g., pyrazolyl, triazolyl) optionally substituted by 1 to 3(preferably 1 or 2, more preferably 1) C₁₋₆ alkyl groups (e.g., methyl).

In the preferable embodiment of the present invention, ring A is

wherein R^(5A) is a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,butylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl) optionallysubstituted by 1 or 2 (preferably 1) substituents selected from a C₁₋₆alkoxy group (e.g., methoxy, ethoxy, tert-butoxy) and a 3- to14-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl,tetrahydropyranyl);

X is CR^(6A) or N; and

R^(6A) is a hydrogen atom or a halogen atom (e.g., fluorine atom).

In another preferable embodiment of the present invention, ring A is

wherein R^(5A) is a 5- to 14-membered aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl)optionally substituted by 1 to 3 (preferably 1 or 2, more preferably 1)C₁₋₆ alkyl groups (e.g., methyl);

X is CR^(6A) or N; and

R^(6A) is a hydrogen atom or a halogen atom (e.g., fluorine atom).

R³ and R⁴ are each independently a hydrogen atom, a halogen atom, ahydroxy group, an optionally substituted C₁₋₆ alkyl group, or anoptionally substituted C₁₋₆ alkoxy group.

Examples of the halogen atom for R³ or R⁴ include a fluorine atom, achlorine atom and a bromine atom, and preferably a fluorine atom.

R³ and R⁴ are preferably each independently a hydrogen atom, a halogenatom, a hydroxy group, a C₁₋₆ alkyl group, or a C₁₋₆ alkoxy group, morepreferably, each independently a hydrogen atom, a halogen atom (e.g.,fluorine atom) or a C₁₋₆ alkyl group (e.g., methyl), further preferably,each independently a hydrogen atom or a halogen atom (e.g., fluorineatom).

In the preferable embodiment of the present invention, R³ and R⁴ areboth hydrogen atoms, or one of R³ and R⁴ is a hydrogen atom, and theother is a halogen atom (e.g., fluorine atom), or one of R³ and R⁴ is ahydrogen atom, and the other is a C₁₋₆ alkyl group (e.g., methyl).

In the more preferable embodiment of the present invention, R³ and R⁴are both hydrogen atoms.

As preferable embodiments of compound (I), the following compounds canbe mentioned.

[Compound I-1]

Compound (I) wherein

R¹ is

(1) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 (preferably 1)hydroxy groups, or(2) a C₃₋₁₀ cycloalkyl group (e.g., cyclobutyl, cyclopentyl, cyclohexyl)optionally substituted by 1 to 3 (preferably 1) substituents selectedfrom a hydroxy group and a halogen atom (e.g., fluorine atom);

R² is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl);

ring A is

(1) a benzene ring optionally further substituted by 1 to 3 (preferably1 or 2, more preferably 1) substituents selected from

(a) a halogen atom (e.g., fluorine atom),

(b) a C₁₋₆ alkoxy group (e.g., methoxy),

(c) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,isobutylcarbamoyl, pentylcarbamoyl) optionally substituted by 1 or 2(preferably 1) substituents selected from

(i) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, tert-butoxy),

(ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclopentyl),

(iii) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydrofuranyl, tetrahydropyranyl),

(iv) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 3(preferably 1) hydroxy groups,

(v) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl),

(vi) a carboxy group,

(vii) a C₁₋₆ alkylthio group (e.g., isopropylthio, tert-butylthio),

(viii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,dimethylcarbamoyl, diethylcarbamoyl), and

(ix) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group (e.g.,pyrrolidin-1-ylcarbonyl),

(d) a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl),

(e) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl) optionallysubstituted by 1 to 3 (preferably 1) hydroxy groups, and

(f) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionallysubstituted by 1 to 3 (preferably 1 or 2, more preferably 1) C₁₋₆ alkylgroups (e.g., methyl),

(2) a 5- or 6-membered monocyclic aromatic heterocycle (e.g., pyridinering) optionally further substituted by 1 to 3 (preferably 1 or 2, morepreferably 1) substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,triazolyl) optionally substituted by 1 to 3 (preferably 1 or 2, morepreferably 1) C₁₋₆ alkyl groups (e.g., methyl),

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle (e.g.,dihydropyridine ring) optionally further substituted by one oxo group,or(4) a 9- to 14-membered fused polycyclic (preferably bicyclic ortricyclic) non-aromatic heterocycle (e.g., isoindoline ring) optionallyfurther substituted by 1 to 3 (preferably 1 or 2) substituents selectedfrom a C₁₋₆ alkyl group (e.g., methyl) and an oxo group; and

R³ and R⁴ are each independently a hydrogen atom, a halogen atom (e.g.,fluorine atom) or C₁₋₆ alkyl group (e.g., methyl).

[Compound I-2]

Compound (I) wherein

R¹ is

(1) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 (preferably 1)hydroxy groups, or(2) a C₃₋₁₀ cycloalkyl group (e.g., cyclobutyl, cyclopentyl, cyclohexyl)optionally substituted by 1 to 3 (preferably 1) substituents selectedfrom a hydroxy group and a halogen atom (e.g., fluorine atom);

R² is a hydrogen atom;

ring A is

(1) a benzene ring optionally further substituted by 1 to 3 (preferably1 or 2, more preferably 1) substituents selected from

(a) a halogen atom (e.g., fluorine atom),

(b) a C₁₋₆ alkoxy group (e.g., methoxy),

(c) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl),and

(d) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, triazolyl, pyridazinyl, pyrimidinyl) optionally substitutedby 1 to 3 (preferably 1 or 2, more preferably 1) C₁₋₆ alkyl groups(e.g., methyl),

(2) a 5- or 6-membered monocyclic aromatic heterocycle (e.g., pyridinering) optionally further substituted by 1 to 3 (preferably 1 or 2, morepreferably 1) substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,triazolyl) optionally substituted by 1 to 3 (preferably 1 or 2, morepreferably 1) C₁₋₆ alkyl groups (e.g., methyl), or

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle (e.g.,dihydropyridine ring) optionally further substituted by one oxo group;and

R³ and R⁴ are each independently a hydrogen atom or a halogen atom(e.g., fluorine atom).

[Compound I-3]

Compound (I) wherein

R¹ is

(1) 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) substituted by one hydroxy group, or(2) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) substituted by 1 to 3(preferably 1) substituents selected from a hydroxy group and a halogenatom (e.g., fluorine atom);

R² is a hydrogen atom;

ring A is

(1) a benzene ring further substituted by 1 to 3 (preferably 1 or 2)substituents selected from

(a) a halogen atom (e.g., fluorine atom),

(b) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl) optionally substituted by 1 or 2 (preferably 1)substituents selected from

(i) a C₁₋₆ alkoxy group (e.g., methoxy), and

(ii) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydrofuranyl), and

(c) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl) optionallysubstituted by 1 to 3 (preferably 1 or 2, more preferably 1) C₁₋₆ alkylgroups (e.g., methyl), or

(2) a 5- or 6-membered monocyclic aromatic heterocycle (e.g., pyridinering) further substituted by one 5- to 14-membered aromatic heterocyclicgroup (e.g., pyrazolyl, triazolyl) optionally substituted by 1 to 3(preferably 1 or 2, more preferably 1) C₁₋₆ alkyl groups (e.g., methyl);and

R³ and R⁴ are each independently a hydrogen atom or a halogen atom(e.g., fluorine atom).

[Compound I-4]

Compound (I) wherein

R¹ is a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) substituted by one hydroxy group;

R² is a hydrogen atom;

ring A is

(1) a benzene ring further substituted by 1 to 3 (preferably 1 or 2)substituents selected from

(a) a halogen atom (e.g., fluorine atom),

(b) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl,ethylcarbamoyl) optionally substituted by 1 or 2 (preferably 1)substituents selected from

(i) a C₁₋₆ alkoxy group (e.g., methoxy), and

(ii) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydrofuranyl), and

(c) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,triazolyl, imidazolyl) optionally substituted by 1 to 3 (preferably 1 or2, more preferably 1) C₁₋₆ alkyl groups (e.g., methyl), or

(2) a 5- or 6-membered monocyclic aromatic heterocycle (e.g., a pyridinering) further substituted by one 5- to 14-membered aromatic heterocyclicgroup (e.g., pyrazolyl, triazolyl) optionally substituted by 1 to 3(preferably 1 or 2, more preferably 1) C₁₋₆ alkyl groups (e.g., methyl);and

R³ and R⁴ are each independently a hydrogen atom or a halogen atom(e.g., fluorine atom).

[Compound I-5]

Compound (I) wherein

R¹ is a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) substituted by one hydroxy group;

R² is a hydrogen atom;

ring A is a benzene ring further substituted by 1 to 3 (preferably 1 or2) substituents selected from

(a) a halogen atom (e.g., fluorine atom),(b) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl)optionally substituted by 1 or 2 (preferably 1) substituents selectedfrom a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydrofuranyl), and(c) a 5- to 14-membered aromatic heterocyclic group (e.g., triazolyl)optionally substituted by 1 to 3 (preferably 1 or 2, more preferably 1)C₁₋₆ alkyl groups (e.g., methyl); and

R³ and R⁴ are each a hydrogen atom.

[Compound I-6]

Compound (I) wherein

R¹ is a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) substituted by one hydroxy group;

R² is a hydrogen atom;

ring A is

wherein R^(5A) is a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,butylcarbamoyl, isobutylcarbamoyl, pentylcarbamoyl) optionallysubstituted by 1 or 2 (preferably 1) substituents selected from a C₁₋₆alkoxy group (e.g., methoxy, ethoxy, tert-butoxy) and a 3- to14-membered non-aromatic heterocyclic group (e.g., tetrahydrofuranyl,tetrahydropyranyl);

X is CR^(6A) or N; and

R^(6A) is a hydrogen atom or a halogen atom (e.g., fluorine atom); and

R³ and R⁴ are each independently a hydrogen atom or a halogen atom(e.g., fluorine atom).

[Compound I-7]

Compound (I) wherein

R¹ is a 3- to 14-membered non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) substituted by one hydroxy group;

R² is a hydrogen atom;

ring A is

wherein R^(5A) is a 5- to 14-membered aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, triazolyl, imidazolyl, pyridazinyl, pyrimidinyl)optionally substituted by 1 to 3 (preferably 1 or 2, more preferably 1)C₁₋₆ alkyl groups (e.g., methyl);

X is CR^(6A) or N; and

R^(6A) is a hydrogen atom or a halogen atom (e.g., fluorine atom); and

R³ and R⁴ are each independently a hydrogen atom or a halogen atom(e.g., fluorine atom).

Specific preferable examples of the compound represented by the formula(I) include the compounds of Examples 1-113.

When compound (I) is in the form of a salt, examples of such saltinclude salts with inorganic base, an ammonium salt, salts with organicbase, salts with inorganic acid, salts with organic acid, salts withbasic or acidic amino acid, and the like.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like; alkaline earthmetal salts such as calcium salt, magnesium salt, barium salt and thelike; an aluminum salt, and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidand the like.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, ornithine and the like.

Preferable examples of the salt with acidic amino acid include saltswith aspartic acid, glutamic acid and the like.

Among these salts, a pharmaceutically acceptable salt is preferable.When a compound has a basic functional group, examples of a preferablepharmaceutically acceptable salt include salts with inorganic acid suchas hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like, and salts with organic acid such as aceticacid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and the like. In addition, when a compound has anacidic functional group, examples thereof include inorganic salts suchas alkali metal salts (e.g., sodium salt, potassium salt etc.), alkalineearth metal salts (e.g., calcium salt, magnesium salt, barium salt etc.)and the like, ammonium salt and the like.

Compound (I) may be a crystal, and both a single crystal and crystalmixtures are encompassed in the compound (I).

Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalsalt. Here, the cocrystal or cocrystal salt means a crystallinesubstance consisting of two or more particular substances which aresolids at room temperature, each having different physical properties(e.g., structure, melting point, heat of melting, hygroscopicity,solubility, stability etc.). The cocrystal and cocrystal salt can beproduced by cocrystallization method known per se.

Compound (I) encompasses solvates (e.g., hydrate) and non-solvateswithin the scope thereof. Compound (I) may be a compound labeled orsubstituted with an isotope (e.g., ²H, ³H, ¹¹C, ¹⁴C, ¹⁸F, ³⁵S, ¹²⁵I). Acompound labeled with or substituted by an isotope can be used, forexample, as a tracer used for Positron Emission Tomography (PET) (PETtracer), and is useful in the field of medical diagnosis and the like.

When compound (I) of the present invention has an asymmetric center,isomers such as enantiomer, diastereomer and the like may be present.Such isomers and a mixture thereof are all encompassed within the scopeof the present invention. When an isomer is formed due to theconformation or tautomerism, such isomers and a mixture thereof are alsoencompassed in compound (I) of the present invention.

The production method of the compound of the present invention isexplained in the following.

The starting materials and reagents used in each step in the followingproduction method, and the obtained compounds each may form a salt.Examples of the salt include those similar to the aforementioned saltsof the compound of the present invention and the like.

When the compound obtained in each step is a free compound, it can beconverted to a desired salt by a method known per se. Conversely, whenthe compound obtained in each step is a salt, it can be converted to afree form or a desired other kind of salt by a method known per se.

The compound obtained in each step can also be used for the nextreaction as a reaction mixture thereof or after obtaining a crudeproduct thereof. Alternatively, the compound obtained in each step canbe isolated and/or purified from the reaction mixture by a separationmeans such as concentration, crystallization, recrystallization,distillation, solvent extraction, fractionation, chromatography and thelike according to a conventional method.

When the starting materials and reagent compounds of each step arecommercially available, the commercially available products can be usedas they are.

In the reaction of each step, while the reaction time varies dependingon the reagents and solvents to be used, unless otherwise specified, itis generally 1 min-48 hr, preferably 10 min-8 hr.

In the reaction of each step, while the reaction temperature variesdepending on the reagents and solvents to be used, unless otherwisespecified, it is generally −78° C. to 300° C., preferably −78° C. to150° C.

In the reaction of each step, while the pressure varies depending on thereagents and solvents to be used, unless otherwise specified, it isgenerally 1 atm-20 atm, preferably 1 atm-3 atm.

In the reaction of each step, for example, microwave synthesizers suchas Initiator manufactured by Biotage and the like are sometimes used.While the reaction temperature varies depending on the reagents andsolvents to be used, unless otherwise specified, it is generally roomtemperature-300° C., preferably 50° C.-250° C. While the reaction timevaries depending on the reagents and solvents to be used, unlessotherwise specified, it is generally 1 min-48 hr, preferably 1 min-8 hr.

In the reaction of each step, unless otherwise specified, a reagent isused in 0.5 equivalent-20 equivalents, preferably 0.8 equivalent-5equivalents, relative to the substrate. When a reagent is used as acatalyst, the reagent is used in 0.001 equivalent-1 equivalent,preferably 0.01 equivalent-0.2 equivalent, relative to the substrate.When the reagent is also a reaction solvent, the reagent is used in asolvent amount.

In the reaction of each step, unless otherwise specified, it isperformed without solvent or by dissolving or suspending in a suitablesolvent. Specific examples of the solvent include those described inExamples and the following.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;saturated hydrocarbons: cyclohexane, hexane and the like; amides:N,N-dimethylformamide, N-methylpyrrolidone and the like;halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;nitriles: acetonitrile and the like;sulfoxides: dimethyl sulfoxide and the like;aromatic organic bases: pyridine and the like;acid anhydrides: acetic anhydride and the like;organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;inorganic acids: hydrochloric acid, sulfuric acid and the like; esters:ethyl acetate and the like;ketones: acetone, methyl ethyl ketone and the like; and water.

Two or more kinds of the above-mentioned solvents may be used by mixingat an appropriate ratio.

When a base is used in the reaction of each step, for example, basesshown below or those described in Examples are used.

inorganic bases: sodium hydroxide, magnesium hydroxide and the like;organic bases: sodium carbonate, calcium carbonate, sodium hydrogencarbonate and the like;organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;alkali metal hydrides: sodium hydride and the like; metal amides: sodiumamide, lithium diisopropyl amide, lithium hexamethyl disilazide and thelike; and organic lithiums: n-butyllithium and the like.

When an acid or an acidic catalyst is used in the reaction of each step,for example, the acids or acidic catalysts shown below or thosedescribed in the Examples are used.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; Lewisacids: boron trifluoride diethyl ether complex, zinc iodide, anhydrousaluminum chloride, anhydrous zinc chloride, anhydrous iron chloride andthe like.

Unless otherwise specified, the reaction of each step is performedaccording to a method known per se, for example, the methods describedin Jikken Kagaku Kouza 5th edition, vol. 13-vol. 19 (The ChemicalSociety of Japan ed.); Shinjikken Kagaku Kouza (Courses in ExperimentalChemistry), vol. 14-vol. 15 (The Chemical Society of Japan ed.); FineOrganic Chemistry rev. 2nd edition (L. F. Tietze, Th. Eicher, NANKODO);rev. Organic Name Reactions, Their Mechanism and Essence (Hideo Togo,Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & SonsInc); Modern Organic Synthesis in the Laboratory, A Collection ofStandard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY);Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier JapanKK); Strategic Applications of Named Reactions in Organic Synthesis(translation supervisor Kiyoshi Tomioka, KAGAKUDOJIN); ComprehensiveOrganic Transformations (VCH Publishers Inc.), 1989 and the like, or themethods described in the Examples.

In each step, protection or deprotection reaction of a functional groupis performed by the method known per se, for example, the methodsdescribed in “Protective Groups in Organic Synthesis, 4th Ed.” (TheodoraW. Greene, Peter G. M. Wuts) Wiley-Interscience, 2007; “ProtectingGroups 3rd Ed.” (P. J. Kocienski) Thieme, 2004 and the like, or themethods described in the Examples.

Examples of the protecting group of the hydroxyl group of alcohol andthe like and a phenolic hydroxyl group include ether protecting groupssuch as methoxymethyl ether, benzyl ether, tert-butyldimethylsilylether, tetrahydropyranyl ether and the like; carboxylate esterprotecting groups such as acetate ester and the like; sulfonate esterprotecting groups such as methanesulfonate ester and the like; carbonateester protecting groups such as tert-butylcarbonate and the like, andthe like.

Examples of the protecting group of the carbonyl group of aldehydeinclude acetal protecting groups such as dimethyl acetal and the like;cyclic acetal protecting groups such as 1,3-dioxane and the like, andthe like.

Examples of the protecting group of the carbonyl group of ketone includeketal protecting groups such as dimethyl ketal and the like; cyclicketal protecting groups such as 1,3-dioxane and the like; oximeprotecting groups such as O-methyloxime and the like; hydrazoneprotecting groups such as N,N-dimethylhydrazone and the like, and thelike.

Examples of the carboxyl protecting group include ester protectinggroups such as methyl ester and the like; amide protecting groups suchas N,N-dimethylamide and the like, and the like.

Examples of the thiol protecting group include ether protecting groupssuch as benzyl thioether and the like; ester protecting groups such asthioacetate ester, thiocarbonate, thiocarbamate and the like, and thelike.

Examples of the protecting group of an amino group and an aromaticheterocycle such as imidazole, pyrrole, indole and the like includecarbamate protecting groups such as benzyl carbamate and the like; amideprotecting groups such as acetamide and the like; alkylamine protectinggroups such as N-triphenylmethylamine and the like, sulfonamideprotecting groups such as methanesulfonamide and the like, and the like.

The protecting group can be removed by a method known per se, forexample, a method using acid, base, ultraviolet light, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyliodide, trimethylsilyl bromide), a reduction method and the like.

When a reduction reaction is performed in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt;hydrogen; formic acid; triethylsilane and the like. When a carbon-carbondouble bond or triple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar catalyst and the like is used.

When an oxidation reaction is performed in each step, examples of anoxidant to be used include peracids such as m-chloroperbenzoic acid(mCPBA), hydrogen peroxide, tert-butyl hydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodic acids such as sodium periodate and thelike; high valent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chrome such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide pyridine complex; osmium tetraoxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When a radical cyclization reaction is performed in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4,4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. In addition, examples of the radical reaction agent to beused include tributylstannane, tristrimethylsilylsilane,1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and thelike.

When the Wittig reaction is performed in each step, examples of theWittig reagent to be used include alkylidenephosphoranes and the like.Alkylidenephosphoranes can be prepared by a method known per se, forexample, by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is performed in each step, examples ofthe reagent to be used include phosphonoacetic acid esters such asmethyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and thelike; and bases such as alkali metal hydrides, organic lithiums and thelike.

When the Friedel-Crafts reaction is performed in each step, examples ofthe reagent to be used include a combination of Lewis acid and acidchloride, a combination of Lewis acid and alkylating agents (e.g., alkylhalides, alcohol, olefins and the like). Alternatively, an organic acidand an inorganic acid can also be used instead of the Lewis acid, andacid anhydride such as acetic anhydride and the like can also be usedinstead of acid chloride.

When an aromatic nucleophilic substitution reaction is performed in eachstep, a nucleophilic agent (e.g., amines, imidazole and the like) and abase (e.g., organic bases and the like) are used as the reagent.

When a nucleophilic addition reaction with carbanion, a nucleophilic1,4-addition reaction with carbanion (Michael addition reaction) or anucleophilic substitution reaction with carbanion is performed in eachstep, examples of the base to be used for developing carbanion includeorganic lithiums, metal alkoxides, inorganic bases, organic bases andthe like.

When the Grignard reaction is performed in each step, examples of theGrignard reagent include aryl magnesium halides such as phenyl magnesiumbromide and the like; and alkyl magnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared bya method known per se, for example, by reacting alkyl halide or arylhalide with metal magnesium in ether or tetrahydrofuran as a solvent.

When the Knoevenagel condensation reaction is performed in each step, anactive methylene compound held between two electron-withdrawing groups(e.g., malonic acid, diethyl malonate, malononitrile and the like) and abase (e.g., organic bases, metal alkoxides, inorganic bases) are used asthe reagents.

When the Vilsmeier-Haack reaction is performed in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide and thelike) are used as the reagents.

When an azidation reaction of alcohols, alkyl halides or sulfonateesters is performed in each step, examples of the azidation agent to beused include diphenylphosphoryl azide (DPPA), trimethylsilyl azide,sodium azide and the like. For example, when alcohols are azidated, amethod using diphenylphosphoryl azide and1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), a method using trimethylsilylazide and the Lewis acid and the like can be employed.

When a reductive amination reaction is performed in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused besides para-formaldehyde include aldehydes such as acetaldehydeand the like, ketones such as cyclohexanone and the like. When thesubstrate is a carbonyl compound, examples of the amines to be usedinclude ammonia, primary amines such as methylamine and the like;secondary amines such as dimethylamine and the like, and the like.

When the Mitsunobu reaction is performed in each step, azodicarboxylateesters (e.g., diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) and the like) and triphenylphosphine are used asthe reagents.

When an esterification reaction, amidation reaction or ureation reactionis performed in each step, examples of the reagent to be used includehalogenated acyl forms such as acid chloride, acid bromide and the like;and activated carboxylic acids such as acid anhydride, active esterform, sulfuric acid ester form and the like. Examples of the carboxylicacid activator include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate ester condensingagents such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; a combination thereof and thelike. When a carbodiimide condensing agent is used, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like can be further added to thereaction.

When a coupling reaction is performed in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride and thelike; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) andthe like; rhodium compounds such as tris(triphenylphosphine)rhodium(III)chloride and the like; a cobalt compound; copper compounds such ascopper oxide, copper(I) iodide and the like; a platinum compound and thelike. A base may be further added to the reaction and examples of suchbase include inorganic bases and the like.

When a thiocarbonylation reaction is performed in each step,diphosphorus pentasulfide is representatively used as athiocarbonylating agent. Besides diphosphorus pentasulfide, a reagenthaving a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) and the like may also be used.

When the Wohl-Ziegler reaction is performed in each step, examples ofthe halogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. Furthermore, the reaction can be accelerated byadding heat, light, radical initiators such as benzoyl peroxide,azobisisobutyronitrile and the like to the reaction.

When a halogenating reaction of a hydroxy group is performed in eachstep, examples of the halogenating agent to be used include acid halideof hydrohalic acid and inorganic acid; specifically, hydrochloric acid,thionyl chloride, phosphorus oxychloride and the like for chlorination,and 48% hydrobromic acid and the like for bromination. In addition, amethod of obtaining an alkyl halide form from alcohol by reacting withtriphenylphosphine and carbon tetrachloride or carbon tetrabromide, andthe like may be used. Alternatively, a method of synthesizing an alkylhalide form via a two-step reaction including conversion of alcohol tosulfonic acid ester, and reacting same with lithium bromide, lithiumchloride or sodium iodide may also be used.

When the Arbuzov reaction is performed in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite, tri(isopropyl)phosphite and the like.

When a sulfonic acid esterification reaction is performed in each step,examples of the sulfonylating agent to be used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic anhydride,p-toluenesulfonic anhydride and the like.

When hydrolysis reaction is performed in each step, an acid or a base isused as the reagent. In addition, when acid hydrolysis reaction oftert-butyl ester is performed, formic acid, triethylsilane and the likeare sometimes added to reductively trap the by-produced tert-butylcation.

When a dehydration reaction is performed in each step, examples of thedehydrating agent to be used include sulfuric acid, phosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

Compound (I) can be produced by the method shown in the followingschemes or a method analogous thereto or the method described inExamples.

Compound (IA) can be produced from compound (1) by the following method.

In the reaction formulas, R⁵ and R⁶ are each a C₁₋₆ alkyl group, R⁷ andR¹⁰ are each a halogen atom, R⁸ is an optionally substituted C₁₋₆ alkylgroup, R⁹ is a cyano group, an optionally substituted C₁₋₆ alkyl group,or an optionally substituted C₁₋₆ alkoxy group, R¹¹ is a hydrogen atom,a cyano group, an optionally substituted C₁₋₆ alkyl group, or anoptionally substituted C₁₋₆ alkoxy group, TMS is a trimethylsilyl group,and R¹, R³, R⁴ and ring A mean the same as above.

Compound (2) can be produced by deprotection of R⁵ which is a protectinggroup of the hydroxy group of compound (1).

Compound (3) can be produced by halogenation of compound (2) and ahalogenating agent such as bromine, iodine and the like.

Compound (4) can be synthesized by Sonogashira coupling reaction ofcompound (3) and trimethylsilylacetylene in the presence of a metalcatalyst and an organic base. As the metal catalyst, a palladiumcompound such as tetrakis(triphenylphosphine)palladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride and the likeand a copper compound such as copper(I) iodide and the like can be usedin combination. As the organic base, triethylamine and diethylamine andthe like can be mentioned.

Compound (5) can be produced by a desilylation reaction of compound (4)with fluoride ion such as potassium fluoride, tetran-butylammoniumfluoride and the like, or a desilylation reaction of compound (4) underbasic conditions such as potassium carbonate and the like or underacidic conditions such as hydrochloric acid and the like.

Compound (6) can be produced by a coupling reaction of compound (5) andbis(pinacolato)diboron in the presence of a metal catalyst.

Compound (7) can be produced by halogenation of compound (4) withN-iodosuccinimide. To the reaction system, a fluoride salt such aspotassium fluoride and the like may be added.

Compound (10) can be produced by a coupling reaction of compound (7) andcompound (8), compound (9) or zinc cyanide in the presence of a metalcatalyst.

Compound (11) can be produced by a coupling reaction of compound (10)and bis(pinacolato)diboron in the presence of a metal catalyst.

Compound (13) can be produced by a coupling reaction of compound (6) orcompound (11) and compound (12) in the presence of a metal catalyst.

Compound (14) can be produced by hydrolysis of compound (13).

Compound (IA) can be produced by an amidation reaction of compound (14)and compound (15).

Compound (13) in the above-mentioned scheme can also be produced fromcompound (16) by the following method.

In the reaction formulas, R¹² is a halogen atom, and R³, R⁴, R⁶, R⁷,R¹⁰, R¹¹ and ring A mean the same as above.

Compound (17) can be produced by halogenation of compound (16) and ahalogenating agent such as bromine, iodine and the like.

Compound (18) can be produced by esterification of compound (17).

Compound (19) can be produced by Sonogashira coupling reaction ofcompound (18) and trimethylsilylacetylene in the presence of a metalcatalyst and an organic base. As the metal catalyst, a palladiumcompound such as tetrakis(triphenylphosphine)palladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride and the likeand a copper compound such as copper(I) iodide and the like can be usedin combination. As the organic base, triethylamine, diethylamine and thelike can be mentioned.

Compound (20) can be produced by a C—H bond activation reaction ofcompound (19) in the presence of a metal catalyst. As the metalcatalyst, an iridium compound such asbis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I),bis(1,5-cyclooctadiene)diiridium(I) dichloride and the like can bementioned, which can be used with a ligand such as 2,2′-bipyridine,4,4′-di-tert-butyl-2,2′-bipyridine and the like for the reaction.

Compound (21) can be produced by a coupling reaction of compound (20)and compound (12) in the presence of a metal catalyst.

Compound (23) can be produced by halogenation of compound (21) with ahalogenating agent such as N-iodosuccinimide, NBS, NCS and the like. Tothe reaction system, a fluoride salt such as potassium fluoride and thelike may be added.

Compound (22) can be produced by a desilylation reaction of compound(21) with fluoride ion such as potassium fluoride, tetran-butylammoniumfluoride and the like, or a desilylation reaction of compound (21) underbasic conditions such as potassium carbonate and the like or underacidic conditions such as hydrochloric acid and the like, or a couplingreaction of compound (23) and compound (8), compound (9) or zinc cyanidein the presence of a metal catalyst.

Compound (IB) can be produced from compound (23) by the followingmethod.

In the reaction formulas, R¹, R³, R⁴, R⁶, R¹² and ring A mean the sameas above.

Compound (24) can be produced by hydrolysis of compound (23).

Compound (IB) can be produced by an amidation reaction of compound (24)and compound (15).

Compound (I′) can be produced from compound (25) by the followingmethod.

In the reaction formulas, R¹, R², R³, R⁴, R⁶ and ring A mean the same asabove.

Compound (26) can be produced by a reduction reaction of compound (25).

Compound (27) can be produced by hydrolysis of compound (26).

Compound (I′) can be produced by an amidation reaction of compound (27)and compound (15).

Compound (26) in the above-mentioned scheme can also be produced fromcompound (28) by the following method.

In the reaction formulas, R², R³, R⁴, R⁶, R⁹, R¹⁰ and ring A mean thesame as above.

Compound (29) can be produced by a reduction reaction of compound (28).

Compound (30) can be produced by a C—H bond activation reaction ofcompound (29) in the presence of a metal catalyst. As the metalcatalyst, an iridium compound such asbis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I),bis(1,5-cyclooctadiene)diiridium(I) dichloride and the like can bementioned, which can be used with a ligand such as 2,2′-bipyridine,4,4′-di-tert-butyl-2,2′-bipyridine and the like for the reaction. Inaddition, compound (30) can also be produced by a reduction reaction ofcompound (6) or (11).

Compound (26) can be produced by a coupling reaction of compound (30)and compound (12) in the presence of a metal catalyst.

Compound (II) which is compound (IA) wherein one of R³ and R⁴ is afluorine atom, and the other is a hydrogen atom can be synthesized fromcompound (31) which is compound (13) or compound (23) wherein R³ and R⁴are each a hydrogen atom by the following method.

In the reaction formulas, R¹, R², R⁶ and ring A mean the same as above.

Compound (32) can be produced by Wohl-Ziegler reaction of compound (31)followed by hydrolysis using acetone-water.

Compound (33) can be produced by fluorination of the hydroxy group ofcompound (32). As the fluorinating agent, (diethylamino)sulfurtrifluoride and the like can be mentioned.

Compound (34) can be produced by hydrolysis of compound (33).

Compound (II) can be produced by an amidation reaction of compound (34)and compound (15).

Compounds (III) and (III′) can be produced from compound (32) by thefollowing method.

In the reaction formulas, R¹³ is an optionally substituted C₁₋₆ alkylgroup, R¹⁴ is a halogen atom, and R¹, R², R⁶ and ring A mean the same asabove.

Compound (35) can be produced by hydrolysis of compound (32).

Compound (III) can be produced by an amidation reaction of compound (35)and compound (15).

Compound (37) can be produced by an alkylation reaction of compound (32)with alkyl halide (36).

Compound (38) can be produced by hydrolysis of compound (37).

Compound (III′) can be produced by an amidation reaction of compound(38) and compound (15).

Of compound (I), compound (IV) wherein ring A has an optionallysubstituted carbamoyl group can be produced from compound (6), compound(11) or compound (30) by the following method.

In the reaction formulas, X is CR^(6A) or N, R¹⁴ and R¹⁵ are eachindependently a hydrogen atom, a halogen atom, an optionally substitutedC₁₋₆ alkyl group, or an optionally substituted C₁₋₆ alkoxy group, R¹⁶ isa protecting group of a carboxyl group, R¹⁷ is a substituent, and R¹,R², R⁶, R¹⁰ and R^(6A) mean the same as above.

Compound (40) can be produced by a coupling reaction of compound (6),compound (11) or compound (30) and compound (39) in the presence of ametal catalyst.

Compound (41) can be produced by hydrolysis of compound (40).

Compound (42) can be produced by an amidation reaction of compound (41)and compound (15).

Compound (43) can be produced by hydrolysis of compound (42).

Compound (IV) can be produced by an amidation reaction of compound (43)and compound (44).

Of compound (I), compound (V) and compounds (V′) wherein one of R³ andR⁴ is a C₁₋₆ alkyl group, and the other is a hydrogen atom, and ring Ahas an optionally substituted carbamoyl group can be produced fromcompound (6) or (11) by the following method.

In the reaction formulas, R¹⁸ is a C₁₋₆ alkyl group, P is a protectinggroup of the phenolic hydroxyl group, Tf is a trifluoromethylsulfonylgroup, TMS is a trimethylsilyl group, and X, R¹, R², R⁶, R¹⁴, R¹⁵ andR¹⁷ mean the same as above.

Compound (46) can be produced by a coupling reaction of compound (6) or(11) and compound (45) in the presence of p-toluenesulfonylhydrazide andan inorganic base according to the method described in (literature)Tetrahedron, 73, 785-793 (2017). As the inorganic base, potassiumcarbonate, potassium phosphate and the like can be mentioned.

Compound (47) can be produced by deprotection of the protecting group ofcompound (46).

Compound (48) can be produced by sulfonic acid esterification ofcompound (47) using trifluoromethanesulfonic anhydride.

Compound (49) can be produced by a carbon monoxide insertion reaction ofcompound (48) in the presence of 2-(trimethylsilyl)ethanol, carbonmonoxide, a base and a metal catalyst.

Compound (50) can be produced by deprotection of compound (49).

Compound (51) can be produced by an amidation reaction of compound (50)and compound (44).

Compound (52) can be produced by hydrolysis of compound (51).

Compound (V) can be produced by an amidation reaction of compound (52)and compound (15).

Compound (53) can be produced by a reduction reaction of compound (51).

Compound (54) can be produced by hydrolysis of compound (53).

Compound (V′) can be produced by an amidation reaction of compound (54)and compound (15).

Compound (1), compound (8), compound (9), compound (12), compound (15),compound (16), compound (28), compound (39), compound (44), compound(45), alkyl halide (36), zinc cyanide, trimethylsilylacetylene,bis(pinacolato)diboron, p-toluenesulfonylhydrazide and2-(trimethylsilyl)ethanol used as starting materials for the productionof compounds (IA), (IB), (I′), (II), (III), (III′), (IV), (V) and (V′)may be commercially available products or can be produced according to amethod known per se.

When compound (I) has an optical isomer, a stereoisomer, a regioisomeror a rotamer, these are also encompassed in compound (I), and can beobtained as a single product according to synthesis and separationmethods known per se. For example, when compound (I) contains an opticalisomer, an optical isomer resolved from the compound is also encompassedin compound (I).

The optical isomer can be produced according to a method known per se.To be specific, an optically active synthetic intermediate is used, orthe final racemate product is subjected to optical resolution accordingto a conventional method to give an optical isomer.

For example, the method of optical resolution may be a method known perse, such as a fractional recrystallization method, a chiral columnmethod, a diastereomer method etc.

1) Fractional Recrystallization Method

A method wherein a salt with a racemate with an optically activecompound (e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,cinchonine, (−)-cinchonidine, brucine etc.) is formed, which isseparated by a fractional recrystallization method, and if desired, aneutralization step to give a free optical isomer.

2) Chiral Column Method

A method wherein a racemate or a salt thereof is applied to a column forseparation of an optical isomer (a chiral column) to allow separation.In the case of a liquid chromatography, for example, a mixture of theoptical isomers is applied to a chiral column such as ENANTIO-OVM(manufactured by Tosoh Corporation), CHIRAL series manufactured byDaicel Corporation and the like, and developed with water, variousbuffers (e.g., phosphate buffer, etc.) and organic solvents (e.g.,ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid,diethylamine etc.), solely or as a mixed solution thereof to separatethe optical isomer.

3) Diastereomer Method

A method wherein a racemic mixture is prepared into a diastereomericmixture by chemical reaction with an optically active reagent, which ismade into a single substance by a typical separation means (e.g., afractional recrystallization method, a chromatography method etc.) andthe like, and is subjected to a chemical treatment such as hydrolysisreaction and the like to remove an optically active reagent moiety,whereby an optical isomer is obtained. For example, when compound (I)contains hydroxy group, or primary or secondary amino group within amolecule, the compound and an optically active organic acid (e.g., MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid etc.) and the like are subjected to condensation reaction to givediastereomers of the ester compound or the amide compound, respectively.When compound (I) has a carboxylic acid group, this compound and anoptically active amine or an optically active alcohol reagent aresubjected to condensation reaction to give diastereomers of the amidecompound or the ester compound, respectively. The separated diastereomeris converted to an optical isomer of the original compound by acidhydrolysis or base hydrolysis reaction.

When compound (I) is obtained as a free compound, the compound can beconverted to an objective salt according to a method known per se or amethod analogous thereto. Conversely, when it is obtained as a salt, thesalt can be converted to a free form or other objective salt by a methodknown per se or a method analogous thereto.

compound (I) may be a prodrug, and the prodrug of compound (I) refers toa compound which is converted to compound (I) as a result of a reactionwith an enzyme, gastric acid, etc. under physiological conditions invivo, thus a compound that undergoes enzymatic oxidation, reduction,hydrolysis etc. to convert to compound (I) and a compound that undergoeshydrolysis and the like by gastric acid, etc. to convert to compound(I).

Examples of the prodrug for compound (I) include a compound obtained bysubjecting an amino group in compound (I) to acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,t-butylation and the like);

a compound obtained by subjecting a hydroxy group in compound (I) toacylation, alkylation, phosphorylation or boration (e.g., a compoundobtained by subjecting a hydroxy group in compound (I) to acetylation,palmitoylation, propanoylation, pivaloylation, succinylation,fumarylation, alanylation or dimethylaminomethylcarbonylation and thelike);a compound obtained by subjecting a carboxyl group in compound (I) toesterification or amidation (e.g., a compound obtained by subjecting acarboxyl group in compound (I) to ethyl esterification, phenylesterification, carboxymethyl esterification, dimethylaminomethylesterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethylesterification, phthalidyl esterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification or methylamidation and thelike) and the like. Any of these compounds can be produced from compound(I) according to a method known per se.

A prodrug of compound (I) may also be one which is converted to compound(I) under physiological conditions as described in “IYAKUHIN no KAIHATSU(Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p.163-198 (HIROKAWA SHOTEN).

Compound (I) may be used for the prophylaxis or treatment of diseases,for example,

(1) constipation, for example, neurogenic constipation (constipationassociated with diseases such as Parkinson's disease, multiplesclerosis, spinal cord injury, Alzheimer's disease, Hirschsprung'ssyndrome, Chagas' disease, and the like), idiopathic constipation,functional constipation, flaccid constipation, irritable bowel syndromewith constipation, constipation possibly complicated by other disease(Parkinson's disease, spinal cord injury, multiple sclerosis, etc.),age-related constipation, various drug-induced constipation (opioidagonist-induced constipation and the like), primary chronicconstipation, drug-induced constipation (opioid, anticholinergic agent,calcium antagonist, anticancer agent, heavy metal toxicosis, and thelike), constipation associated with underlying diseases such asendocrine diseases or metabolic abnormality (hypopituitarism,hypothyroidism, pheochromocytoma, and the like), muscle abnormalitiesdisease (familial visceral skeletal muscle atrophy, scleroderma,amyloidosis, progressive systemic sclerosis, and the like), metabolicdiseases (diabetes, porphyria, uremia, hypokalemia, hypercalcemia, andthe like) and the like,(2) digestive diseases [e.g., gastric ulcer, duodenal ulcer, gastrichypomotility such as gastroparalysis and the like, post-operativegastrointestinal paralysis, upper gastrointestinal motility disorder anddiscomfort, nausea, vomiting, erosive esophagitis, antiinflammatoryagents (non-steroidal antiinflammatory agents)-induced gastrointestinaldisorder, irritable bowel syndrome, inflammatory bowel disease,ulcerative colitis, Crohn's disease, stress gastrointestinal disorder,diarrhea, postoperative ileus],(3) psychiatric diseases [e.g., depression, major depression, bipolardepression, dysthymic disorder, emotional disorder (seasonal affectivedisorder and the like), recurrent depression, postpartum depression,stress disorder, depression symptom, mania, generalized anxietydisorder, anxiety syndrome, panic disorder, phobia, social phobia,social anxiety disorder, obsessive disorder, post-traumatic stresssyndrome, post-traumatic stress disorder, Tourette syndrome, autism,autism spectrum syndrome, fragile X syndrome, Rett syndrome, adjustmentdisorder, bipolar disorder, neurosis, schizophrenia (e.g., positivesymptom, negative symptom, and cognitive impairment), cognitiveimpairment associated with schizophrenia, chronic fatigue syndrome,anxiety neurosis, compulsive neurosis, epilepsy, anxiety symptom,anxious mental state, emotional abnormality, cyclothymia, nervouserethism, faint, addiction, low sex drive, attention deficithyperactivity disorder (ADHD), psychotic major depression, intractablemajor depression, treatment-resistant depression],(4) neurodegenerative diseases [e.g., Alzheimer's disease,Alzheimer-type senile dementia, Parkinson's disease, Parkinson's diseasedementia, Huntington's disease, multi-infarct dementia, frontotemporaldementia, frontotemporal dementia Parkinson's Type, progressivesupranuclear palsy, Pick's syndrome, Niemann-Pick syndrome, corticobasaldegeneration, Down's syndrome, vascular dementia, postencephaliticparkinsonism, Lewy body dementia, HIV dementia, amyotrophic lateralsclerosis (ALS), motor neurogenesis disease (MND), Creutzfeldt-Jakobdisease or prion disease, cerebral palsy, multiple sclerosis],(5) age-related cognition and memory disorders [e.g., age-related memorydisorders, senile dementia],(6) sleep disorders [e.g., intrinsic sleep disorders (e.g.,psychophysiological insomnia and the like), extrinsic sleep disorder,circadian rhythm disorders (e.g., time zone change syndrome (jet lag),shift work sleep disorder, irregular sleep-wake pattern, delayed sleepphase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wakeand the like), parasomnia, sleep disorders associated with internalmedical or psychiatric disorder (e.g., chronic obstructive pulmonarydiseases, Alzheimer's disease, Parkinson's disease, cerebrovasculardementia, schizophrenia, depression, anxiety neurosis), stress insomnia,insomnia, insomniac neurosis, sleep apnea syndrome],(7) respiratory depression caused by anesthetics, traumatic disease, orneurodegenerative disease and the like,(8) traumatic brain injury, cerebral apoplexy, neurotic anorexia, eatingdisorder, anorexia nervosa, hyperorexia, other eating disorder, alcoholdependence, alcohol abuse, alcoholic amnesia, alcohol paranoia, alcoholpreference, alcohol withdrawal, alcoholic insanity, alcohol poisoning,alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatricdisorder, alcoholic insanity, pharmacophilia, pharmacophobia,pharmacomania, drug withdrawal, migraine, stress headache, catatonicheadache, diabetic neuropathy, obesity, diabetes, muscular convulsion,Meniere's disease, autonomic ataxia, alopecia, glaucoma, hypertension,cardiac disease, tachycardia, congestive cardiac failure, hyperpnea,bronchial asthma, apnea, sudden infant death syndrome, inflammatorydisease, allergic disease, impotence, climacteric disorder, infertility,cancer, immunodeficiency syndrome caused by HIV infection,immunodeficiency syndrome caused by stress, cerebrospinal meningitis,acromegaly, metabolic syndrome, osteoporosis, incontinence, dysuria,bladder functional disorder,(9) pain, and the like in mammals (e.g., mouse, rat, hamster, rabbit,cat, dog, bovine, sheep, monkey, human etc.). Particularly preferably,compound (I) may be used for the prophylaxis or treatment of neurogenicconstipation (constipation associated with diseases such as Parkinson'sdisease, multiple sclerosis, spinal cord injury, Alzheimer's disease,Hirschsprung's syndrome, Chagas' disease, and the like), idiopathicconstipation, functional constipation, flaccid constipation, irritablebowel syndrome with constipation, constipation possibly complicated byother disease (Parkinson's disease, spinal cord injury, multiplesclerosis, etc.), age-related constipation, various drug-inducedconstipation (opioid agonist-induced constipation and the like), primarychronic constipation, drug-induced constipation (opioid, anticholinergicagent, calcium antagonist, anticancer agent, heavy metal toxicosis, andthe like), constipation associated with underlying diseases such asendocrine diseases or metabolic abnormality (hypopituitarism,hypothyroidism, pheochromocytoma, and the like), muscle abnormalitiesdisease (familial visceral skeletal muscle atrophy, scleroderma,amyloidosis, progressive systemic sclerosis, and the like), metabolicdiseases (diabetes, porphyria, uremia, hypokalemia, hypercalcemia, andthe like) and the like.

Since compound (I) may have a cholinergic muscarinic M1 receptorpositive allosteric modulator activity, it is expected to provide anexcellent prophylactic or therapeutic effect for the above-mentioneddiseases.

Generally, it is desirable that the therapeutic drugs for constipationexhibit effect promptly after administration and then the effectdisappears quickly. Compound (I) is expected to show superiorpharmacokinetics as a therapeutic drug for constipation and may beexpected to exhibit effect within, for example, 3 hr afteradministration, preferably 2 hr after administration, further preferably1 hr after administration, and the effect may be expected to disappearquickly thereafter.

Cholinergic muscarinic M1 receptor is known to express in the brain andgastrointestinal nerve plexus. Compound (I) is expected to show lowcentral nervous system permeability, function efficiently in peripheryand show excellent effect as a therapeutic drug for constipation.Regarding central nervous system permeability, for example, correctedefflux ratio of MDR1 in MDR1 membrane permeability test is preferablynot less than 2.0, more preferably not less than 3.0, and furthermorepreferably not less than 5.0.

Since compound (I) may be expected to be excellent in solubility inwater, the Japanese Pharmacopoeia dissolution test 2nd fluid, or theJapanese Pharmacopoeia disintegration test 2nd fluid, excellent inpharmacokinetics (e.g., plasma drug half-life, metabolic stability, CYPinhibition), show low toxicity (e.g., more excellent as a medicament interms of acute toxicity, chronic toxicity, genetic toxicity,reproductive toxicity, cardiotoxicity, drug interaction,carcinogenicity, phototoxicity and the like), and may also haveexcellent properties as a pharmaceutical product such as a few sideeffects and the like, it can be safely administered orally orparenterally to a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog,bovine, sheep, monkey, human and the like). Examples of the “parenteral”include intravenous, intramuscular, subcutaneous, intra-organ,intranasal, intradermal, instillation, intracerebral, intrarectal,intravaginal, intraperitoneal and intratumor administrations,administration to the vicinity of tumor etc. and direct administrationto the lesion.

A medicament containing compound (I) (sometimes to be abbreviated as“medicament of the present invention” in the present specification) mayhave any form (preparation form) of a solid preparation such as powder,granule, tablet, capsule, orally disintegrable film and the like, or aliquid agent such as syrup, emulsion, injection and the like.

The medicament of the present invention may be produced by aconventional method such as blending, kneading, granulation, tableting,coating, sterilization treatment, emulsification and the like accordingto the form of the preparation. As for the production of thepreparation, for example, each item of the Japanese PharmacopoeiaPreparation General Rules and the like can be referred to. In addition,the medicament of the present invention may be formed into asustained-release preparation containing an active ingredient and abiodegradable polymer compound. The sustained-release preparation can beproduced according to the method described in JP-A-9-263545.

In the medicament of the present invention, the content of compound (I)varies depending on the form of the preparation, but is generally 0.01to 100% by weight, preferably 0.1 to 50% by weight, more preferably 0.5to 20% by weight, as the amount of compound (I) relative to the wholepreparation (whole medicament).

Compound (I) may be used alone or in admixture with a suitable,pharmacologically acceptable carrier, for example, excipients (e.g.,starch, lactose, white soft sugar, calcium carbonate, calcium phosphate,etc.), binders (e.g., starch, arabic gum, carboxymethyl cellulose,hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin,polyvinylpyrrolidone, etc.), lubricants (e.g., stearic acid, magnesiumstearate, calcium stearate, talc, etc.), disintegrants (e.g., calciumcarboxymethylcellulose, talc, etc.), diluents (e.g., water forinjection, physiological saline, etc.) and if desired, with theadditives (e.g., a stabilizer, a preservative, a colorant, a fragrance,a solubilizing agent, an emulsifier, a buffer, an isotonic agent, etc.)and the like, by a conventional method, which is processed into a dosageform of a solid agent such as powder, fine granule, granule, tablet,capsule and the like or a liquid form such as injection and the like,and administered orally or parenterally. When compound (I) is formed asa preparation for topical administration, it can also be directlyadministered to the affected part of an articular disease. In this case,an injection is preferable. Compound (I) can also be administered as aparenteral agent for topical administration (e.g., intramuscularinjection, subcutaneous injection, organ injection, injection to thevicinity of a joint and the like, solid preparation such as implant,granule, powder and the like, liquid such as suspension and the like,ointment etc.) and the like.

For formulation into an injection, for example, compound (I) isformulated into an aqueous suspension with a dispersing agent (e.g.,surfactant such as Tween 80, HCO-60 and the like, polysaccharides suchas carboxymethylcellulose, sodium alginate, hyaluronic acid and thelike, polysorbate etc.), preservative (e.g., methylparaben,propylparaben etc.), isotonic agent (e.g., sodium chloride, mannitol,sorbitol, glucose etc.), buffer (e.g., calcium carbonate etc.), pHadjuster (e.g., sodium phosphate, potassium phosphate etc.) and the liketo give a practical preparation for injection. In addition, an oilysuspension can be obtained by dispersing the compound together withvegetable oil such as sesame oil, corn oil and the like or a mixturethereof with a phospholipid such as lecithin and the like, ormedium-chain fatty acid triglyceride (e.g., miglyol 812 etc.) to give aninjection to be actually used.

The dose of compound (I) varies depending on the subject ofadministration, administration route and symptoms and is notparticularly limited. For example, for oral administration to adultpatients (body weight adult 40 to 80 kg, for example, 60 kg) withconstipation, the dose may be, for example, 0.001 to 1000 mg/kg bodyweight/day, preferably 0.01 to 100 mg/kg body weight/day, morepreferably 0.1 to 10 mg/kg body weight/day, as compound (I). This amountmay be administered in one to three portions per day.

The medicament of the present invention may be able to use the compound(I) solely or as a pharmaceutical composition of compound (I) mixed witha pharmacologically acceptable carrier according to a method known perse (e.g., the method described in the Japanese Pharmacopoeia etc.) asthe production method of a pharmaceutical preparation. The medicament ofthe present invention may be administered safely in the form of, forexample, a pharmaceutical composition such as tablet (includingsugar-coated tablet, film-coated tablet, sublingual tablet, orallydisintegrating tablet, buccal and the like), pill, powder, granule,capsule (including soft capsule, microcapsule), troche, syrup, liquid,emulsion, suspension, release control preparation (e.g.,immediate-release preparation, sustained-release preparation,sustained-release microcapsule), aerosol, film (e.g., orallydisintegrating film, oral mucosa-adhesive film), injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, transdermal absorption typepreparation, ointment, lotion, adhesive preparation, suppository (e.g.,rectal suppository, vaginal suppository), pellet, nasal preparation,pulmonary preparation (inhalant), eye drop and the like, orally orparenterally (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, instillation, intracerebral,intrarectal, intravaginal, intraperitoneal, lesion and the like).

As the aforementioned “pharmacologically acceptable carrier”, variousorganic or inorganic carriers conventionally used as preparationmaterials (starting materials) may be used. For example, excipient,lubricant, binder, disintegrant and the like may be used for solidpreparations, and solvent, solubilizing agent, suspending agent,isotonic agent, buffer, soothing agent and the like may be used forliquid preparations. Where necessary, preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like mayalso be used.

Examples of the excipient include lactose, white soft sugar, D-mannitol,starch, corn starch, crystalline cellulose, light anhydrous silicic acidand the like.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, white soft sugar,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, sodium carboxymethyl starch,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffer include buffer solutions such as phosphate salts,acetate salts, carbonate salts, citrate salts and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of the antioxidant include sulfite salts, ascorbic acid,α-tocopherol and the like.

While the pharmaceutical composition varies according to the dosageform, administration method, carrier and the like, it may be producedaccording to a conventional method by adding compound (I) in aproportion of generally 0.01-100% (w/w), preferably 0.1-95% (w/w), ofthe total amount of the preparation.

Compound (I) may be used in combination with other active ingredients(hereinafter to be abbreviated as concomitant drug)

Examples of the concomitant drug include the following.

Prokinetic agent (cholinesterase inhibitor (neostigmine, physostigmineetc.), 5-HT₄ agonist, ghrelin agonist (capromorelin etc.), motilinreceptor agonist (camicinal, erythromycin etc.), opioid antagonist(naltrexone, naloxegol etc.)), intestinal water secretion promoter(guanylate cyclase C agonist (linaclotide etc.), chloride channel 2opener (lubiprostone etc.), sodium/proton exchanger 3 inhibitor(tenapanor etc.)), anti-constipation drug (sennoside, magnesium oxide,magnesium hydroxide, bisacodyl, polycarbophil calcium, laxative sugars(lactulose etc.), laxoberon, crude drug having an anti-constipationaction (psyllium etc.) etc.), benzodiazepine (chlordiazepoxide,diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolametc.), L-type calcium channel inhibitor (pregabalin etc.), tricyclic ortetracyclic antidepressant (imipramine hydrochloride, amitriptylinehydrochloride, desipramine hydrochloride, clomipramine hydrochlorideetc.), selective serotonin reuptake inhibitor (fluvoxamine maleate,fluoxetine hydrochloride, citalopram hydrobromide, sertralinehydrochloride, paroxetine hydrochloride, escitalopram oxalate etc.),serotonin-noradrenaline reuptake inhibitor (venlafaxine hydrochloride,duloxetine hydrochloride, desvenlafaxine hydrochloride etc.),noradrenaline reuptake inhibitor (reboxetine mesylate etc.),noradrenaline-dopamine reuptake inhibitor (bupropion hydrochlorideetc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride,bupropion hydrochloride, setiptiline maleate, 5-HT_(1A) agonist(buspirone hydrochloride, tandospirone citrate, osemozotan hydrochlorideetc.), 5-HT₃ antagonist (cyamemazine etc.), non-cardioselective βblocker (propranolol hydrochloride, oxprenolol hydrochloride etc.),histamine H₁ antagonist (hydroxyzine hydrochloride etc.), therapeuticdrug for schizophrenia (chlorpromazine, haloperidol, sulpiride,clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride,olanzapine, quetiapine fumarate, risperidone, aripiprazole etc.), CRFantagonist, other antianxiety drug (meprobamate etc.), tachykininantagonist (aprepitant, saredutant etc.), medicament that acts onmetabotropic glutamate receptor, CCK antagonist, β3 adrenalineantagonist (amibegron hydrochloride etc.), GAT-1 inhibitor (tiagabinehydrochloride etc.), N-type calcium channel inhibitor, carbonicanhydrase II inhibitor, NMDA glycine moiety agonist, NMDA antagonist(memantine etc.), peripheral benzodiazepine receptor agonist,vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1aantagonist, phosphodiesterase inhibitor, opioid agonist, uridine,nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAOinhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemideetc.), 5-HT_(2A) antagonist, 5-HT_(2A) inverse agonist, COMT inhibitor(entacapone etc.), therapeutic drug for bipolar disorder (lithiumcarbonate, sodium valproate, lamotrigine, riluzole, felbamate etc.),cannabinoid CB1 antagonist (rimonabant etc.), FAAH inhibitor, sodiumchannel inhibitor, anti-ADHD drug (methylphenidate hydrochloride,methamphetamine hydrochloride etc.), therapeutic drug for alcoholism,therapeutic drug for autisma, therapeutic drug for chronic fatiguesyndrome, therapeutic drug for convulsion, therapeutic drug forfibromyalgia syndrome, therapeutic drug for headache, therapeutic drugfor insomnia (etizolam, zopiclone, triazolam, zolpidem, ramelteon,indiplon etc.), therapeutic drug for quitting smoking, therapeutic drugfor myasthenia gravis, therapeutic drug for cerebral infarction,therapeutic drug for mania, therapeutic drug for hypersomnia,therapeutic drug for pain, therapeutic drug for dysthymia, therapeuticdrug for autonomic ataxia, therapeutic drug for male and female sexualdysfunction, therapeutic drug for migraine, therapeutic drug forpathological gambler, therapeutic drug for restless legs syndrome,therapeutic drug for substance addiction, therapeutic drug foralcohol-related syndrome, therapeutic drug for irritable bowel syndrome,therapeutic drug for Alzheimer's disease (donepezil, galanthamine,memantine, rivastigmine etc.), therapeutic drug for Parkinson's disease(levodopa, carbidopa, benserazide, selegiline, rasagiline, zonisamide,entacapone, amantadine, talipexole, pramipexole, ropinirole, rotigotine,apomorphine, cabergoline, pergolide, bromocriptine, istradefylline,trihexyphenidyl, biperiden, piroheptine, profenamine, promethazine,droxidopa, combination of those drugs etc.), therapeutic drug forParkinson's disease dementia (rivastigmine), therapeutic drug for Lewybody dementia (donepezil), therapeutic drug for ALS (riluzole,neurotrophic factor etc.), therapeutic drug for lipid abnormality suchas cholesterol-lowering drug (statin series (pravastatin sodium,atorvastatin, simvastatin, rosuvastatin etc.), fibrate (clofibrateetc.), squalene synthetase inhibitor), therapeutic drug for behaviorabnormalities or suppressant of dromomania due to dementia (sedatives,antianxiety drug etc.), apoptosis inhibitor, antiobesity drug,therapeutic drug for diabetes, therapeutic drug for hypertension,therapeutic drug for hypotension, therapeutic drug for rheumatism(DMARD), anti-cancer agent, therapeutic drug for hypothyroidism (PTH),calcium receptor antagonist, sex hormone or a derivative thereof(progesterone, estradiol, estradiol benzoate etc.), neuronaldifferentiation promoter, nerve regeneration promoter, non-steroidalanti-inflammatory drug (meloxicam, tenoxicam, indomethacin, ibuprofen,celecoxib, rofecoxib, aspirin etc.), steroid (dexamethasone, cortisoneacetate etc.), anti-cytokine drug (TNF inhibitor, MAP kinase inhibitoretc.), antibody medicament, nucleic acid or nucleic acid derivative,aptamer drug and the like.

By combining compound (I) and a concomitant drug, a superior effect suchas

(1) the dose may be reduced as compared to single administration of thecompound (I) or a concomitant drug,(2) the drug to be combined with the compound (I) may be selectedaccording to the condition of patients (mild case, severe case and thelike),(3) the period of treatment may be set longer by selecting a concomitantdrug having different action and mechanism from the compound (I),(4) a sustained treatment effect may be designed by selecting aconcomitant drug having different action and mechanism from the compound(I),(5) a synergistic effect may be afforded by a combined use of thecompound (I) and a concomitant drug, and the like, can be achieved.

Hereinafter compound (I) and a concomitant drug used in combination arereferred to as the “combination agent of the present invention”.

When using the combination agent of the present invention, theadministration time of compound (I) and the concomitant drug is notrestricted, and compound (I) or a pharmaceutical composition thereof andthe concomitant drug or a pharmaceutical composition thereof can beadministered to an administration subject simultaneously, or may beadministered at different times. The dosage of the concomitant drug maybe determined according to the dose clinically used, and can beappropriately selected depending on an administration subject,administration route, disease, combination and the like.

The administration mode of the combination agent of the presentinvention is not particularly restricted, and it is sufficient thatcompound (I) and the concomitant drug are combined in administration.Examples of the administration mode include the following methods:

(1) administration of a single preparation obtained by simultaneouslyprocessing compound (I) and the concomitant drug,(2) simultaneous administration of two kinds of preparations of compound(I) and the concomitant drug, which have been separately produced, bythe same administration route, (3) administration of two kinds ofpreparations of compound (I) and the concomitant drug, which have beenseparately produced, by the same administration route in a staggeredmanner, (4) simultaneous administration of two kinds of preparations ofcompound (I) and the concomitant drug, which have been separatelyproduced, by different administration routes, (5) administration of twokinds of preparations of compound (I) and the concomitant drug, whichhave been separately produced, by different administration routes in astaggered manner (e.g., administration in the order of compound (I) andthe concomitant drug, or in the reverse order) and the like.

The combination agent of the present invention can be expected to showlow toxicity. For example, compound (I) or(and) the aforementionedconcomitant drug can be combined with a pharmacologically acceptablecarrier according to the known method to prepare a pharmaceuticalcomposition such as tablets (including sugar-coated tablet andfilm-coated tablet), powders, granules, capsules (including softcapsule), liquids, injections, suppositories, sustained-release agents,etc. These compositions may be administered safely orally or non-orally(e.g., topical, rectal, intravenous administration etc.) Injection maybe administered intravenously, intramuscularly, subcutaneously, or byintraorgan administration or directly to the lesion.

As the pharmacologically acceptable carriers that may be used for theproduction of a combination agent in the present invention, variousorganic or inorganic carrier substances conventionally used aspreparation materials may be used. For solid preparations, for example,excipient, lubricant, binder and disintegrant may be used. For liquidpreparations, for example, solvent, solubilizing agent, suspendingagent, isotonic agent, buffering agent, soothing agent and the like maybe used. Where necessary, a suitable amount of conventionalpreservative, antioxidant, colorant, sweetening agent, adsorbent,wetting agent and the like may be used as appropriate.

Examples of the excipient include lactose, white soft sugar, D-mannitol,starch, corn starch, crystalline cellulose, light anhydrous silicic acidand the like.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, white soft sugar,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, sodium carboxymethyl starch,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffer include buffer solutions such as phosphate salts,acetate salts, carbonate salts, citrate salts and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of the antioxidant include sulfite salts, ascorbic acid,α-tocopherol and the like.

The mixing ratio of compound (I) to the concomitant drug in thecombination agent of the present invention can be appropriately selecteddepending on an administration subject, administration route, diseasesand the like.

For example, the content of compound (I) in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to 100 wt %, preferably from about 0.1 to 50 wt%, further preferably from about 0.5 to 20 wt %, based on the wholepreparation.

The content of the concomitant drug in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to 100 wt %, preferably from about 0.1 to 50 wt%, further preferably from about 0.5 to 20 wt %, based on the wholepreparation.

The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 1 to 99.99 wt %, preferablyfrom about 10 to 90 wt %, based on the whole preparation.

When compound (I) and a concomitant drug are separately formulated intopreparations, the contents thereof are similar to the above.

EXAMPLE

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples,which are not to be construed as limitative, and the invention may bechanged within the scope of the present invention.

In the following Examples, the “room temperature” generally means about10° C. to about 35° C. The ratios indicated for mixed solvents arevolume mixing ratios, unless otherwise specified. % means wt %, unlessotherwise specified.

Elution in column chromatography in the Examples was performed underobservation by TLC (Thin Layer Chromatography) unless particularlyindicated. In the TLC observation, 60 F₂₅₄ manufactured by Merck wasused as a TLC plate, and the solvent used as an eluent in the columnchromatography was used as an elution solvent. For detection, a UVdetector was employed. In silica gel column chromatography, theindication of NH means use of aminopropylsilane-bonded silica gel, andthe indication of Diol means use of3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparativeHPLC (high performance liquid chromatography), the indication of C18means use of octadecyl-bonded silica gel. The ratio of elution solventsis, unless otherwise specified, a volume mixing ratio.

For the analysis of ¹H NMR, ACD/SpecManager (trade name) software andthe like were used. Very mild peaks for protons of a hydroxy group, anamino group and the like may not be described.

MS was measured by LC/MS. As ionization method, ESI method or APCImethod was used. The data indicates those found. Generally, molecularion peaks are observed but may sometimes be observed as a fragment ion.In the case of a salt, generally, a molecular ion peak or a fragment ionpeak of a free form is observed.

The unit of the sample concentration (c) by optical rotation ([α]_(D))is g/100 mL.

Elemental analytical value (Anal.) shows calculated value (Calcd) andmeasured value (Found).

The peak in powder X-ray diffraction in the Examples means a peakmeasured using Cu Kα ray as a radiation source and Ultima IV (RigakuCorporation, Japan) at room temperature. The measurement conditions areas follows.

Electric pressure/Electric current: 40 kV/50 mA

Scan speed: 6 degree/min

Scan range of 2 Theta: 2-35 degree

The crystallinity by powder X-ray diffraction in the Examples wascalculated by the Hermans method.

In Examples, the following abbreviations are used.

mp: melting pointMS: mass spectrumM: mol concentrationN: normalityCDCl₃: deuterochloroformDMSO-d₆: hexadeuterodimethyl sulfoxide¹H NMR: proton nuclear magnetic resonanceLC/MS: liquid chromatograph mass spectrometerESI: electrospray ionizationAPCI: atmospheric pressure chemical ionizationAIBN: 2,2′-azobis(isobutyronitrile)DAST: (diethylamino)sulfur trifluorideDCM: dichloromethane

DIPEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide

DME: 1,2-dimethoxyethane

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxideDMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride n-hydrateEtOH: ethanolHATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHOBt: 1-hydroxybenzotriazoleHOBt.H₂O: 1-hydroxybenzotriazole hydrateIPE: diisopropyl etherLAH: lithium aluminum hydrideMeOH: methanolMEK: methyl ethyl ketone

NBS: N-bromosuccinimide

Pd(PPh₃)₄: tetrakis (triphenylphosphine)palladium(0)Pd₂(dba)₃: tris (dibenzylideneacetone)dipalladium(0)PdCl₂(dppf): [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridePdCl₂(dppf).DCM: [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complexTEA: triethylamineTFA: trifluoroacetic acidTHF: tetrahydrofuranWSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideWSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloridetRn(n=1-4): retention time by high performance liquid chromatography(number shows the order of elution)

Example 1N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) methyl 4-chloro-5-hydroxypyridine-2-carboxylate

To a mixture of methyl 4-chloro-5-methoxypyridine-2-carboxylate (3.85 g)and anhydrous DCM (200 mL) was added aluminum chloride (25.5 g) at roomtemperature, and the mixture was heated under reflux under a nitrogenatmosphere for 16 hr. The reaction mixture was added to ice water (150mL) to terminate the reaction, and the mixture was extracted withDCM/THF (10:1). The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give the titlecompound (3.15 g).

¹H NMR (400 MHz, CDCl₃) δ 3.98 (3H, s), 5.61 (1H, brs), 8.18 (1H, s),8.46 (1H, s).

B) methyl 4-chloro-5-hydroxy-6-iodopyridine-2-carboxylate

To a mixture of methyl 4-chloro-5-hydroxypyridine-2-carboxylate (15.1g), potassium carbonate (11.1 g) and water (150 mL) was added iodine(30.8 g) at room temperature, and the mixture was stirred at 50° C. for16 hr. The solid was filtered off, and the filtrate was washed withethyl acetate. To the aqueous layer was added saturated aqueous sodiumthiosulfate solution, and the mixture was adjusted to pH 1 withconcentrated hydrochloric acid and extracted with ethyl acetate/THF(1/1). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give the title compound (23.5 g).

¹H NMR (400 MHz, CDCl₃) δ 3.95 (3H, s), 5.90 (1H, brs), 8.06 (1H, s).

C) methyl 7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of methyl 4-chloro-5-hydroxy-6-iodopyridine-2-carboxylate(24.5 g), trimethylsilylacetylene (8.05 g), PdCl₂(dppf) (2.75 g),copper(I) iodide (745 mg), TEA (31.6 mL) and dehydrated THF (300 mL) wasstirred under a nitrogen atmosphere at 10° C. for 16 hr. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (14.4 g).

¹H NMR (400 MHz, CDCl₃) δ 0.41 (9H, s), 4.04 (3H, s), 7.25 (1H, s), 8.14(1H, s).

D) methyl 7-chlorofuro[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate (14.4 g)and dehydrating MeOH (200 mL) was added potassium fluoride (8.85 g), andthe mixture was stirred at 10° C. for 16 hr. The solvent was evaporatedunder reduced pressure, water was added to the residue, and the mixturewas extracted with ethyl acetate/THF (1/1). The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to give the title compound (9.12 g).

MS: [M+H]⁺ 211.8.

E) methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of bis(pinacolato)diboron (9.00 g), methyl7-chlorofuro[3,2-b]pyridine-5-carboxylate (5.00 g),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.811 g),potassium acetate (4.64 g) and dehydrated THF (100 mL) was addedPd₂(dba)₃ (0.782 g) at room temperature. The mixture was stirred under anitrogen atmosphere at 65° C. for 3 hr and cooled to room temperature.The mixture was diluted with ethyl acetate and added to water, and theprecipitated solid was filtered off. The filtrate was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. To the residue was added IPE, andthe solid was collected by filtration and washed with IPE to give thetitle compound (3.77 g).

¹H NMR (300 MHz, CDCl₃) δ 1.43 (12H, s), 4.04 (3H, s), 7.11 (1H, d,J=2.6 Hz), 8.02 (1H, d, J=2.3 Hz), 8.50 (1H, s).

F) methyl 7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate(150 mg), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (95 mg), sodiumcarbonate (105 mg), DME (3.0 mL) and water (1.0 mL) was addedPdCl₂(dppf) (18.1 mg) at room temperature. Under an argon atmosphere,the mixture was stirred at 80° C. for 1 hr, diluted with ethyl acetateat room temperature, and added to water. The organic layer was washedwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (114 mg).

MS: [M+H]⁺ 334.2.

G) methyl7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate (2.55 g),10% palladium-carbon (1.25 g) and EtOH (150 mL) was stirred under ahydrogen atmosphere of 55 psi (3.79 kPa) at 20° C. for 3 days. Thecatalyst was filtered off, and the filtrate was concentrated underreduced pressure to give the title compound (2.04 g).

¹H NMR (400 MHz, CDCl₃) δ 3.42 (2H, t, J=8.8 Hz), 3.91-3.96 (5H, m),4.76 (2H, t, J=8.8 Hz), 6.45 (1H, t, J=2.0 Hz), 7.30 (2H, d, J=8.4 Hz),7.62 (2H, d, J=8.4 Hz), 7.71 (1H, d, J=1.2 Hz), 7.79 (1H, s), 7.89 (1H,d, J=2.4 Hz).

H)7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

A mixture of methyl7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate(2.04 g), lithium hydroxide monohydrate (1.28 g) and THF/MeOH/water(3/1/1, 35 mL) was stirred at 10° C. for 16 hr. The solvent wasevaporated under reduced pressure. To a mixture of the residue and water(50 mL) was added concentrated hydrochloric acid to adjust pH to 1, andthe mixture was stirred at 10° C. for 0.5 hr. The precipitated solid wascollected by filtration and dried to give the title compound (1.50 g).

MS: [M+H]⁺ 321.9.

I)N-((1S,2S)-2-hydroxycyclopentyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

A mixture of7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid (360 mg), (1S,2S)-2-aminocyclopentanol hydrochloride (232 mg),WSC.HCl (439 mg), HOBt (151 mg), DIPEA (433 mg) and DMF (10 mL) wasstirred under a nitrogen atmosphere at 10° C. for 16 hr. The mixture wasadded to water and extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified bypreparative thin layer chromatography (petroleum ether/ethyl acetate) togive the title compound (310 mg).

Example 4N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxamideA) 7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxylic acid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 320.2.

B)N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 5N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)furo[3,2-b]pyridine-5-carboxamideA) methyl7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 348.1.

B)7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 334.1.

C)N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)furo[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 81,5-anhydro-2,4-dideoxy-2-(((7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

MS: [M+H]⁺ 350.1.

B)7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 336.1.

C)1,5-anhydro-2,4-dideoxy-2-(((7-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 10N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-methoxypyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) methyl7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 299.1.

B) methyl7-((6-methoxypyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

MS: [M+H]⁺ 301.1.

C)7-((6-methoxypyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 287.2.

D)N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-methoxypyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 12N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-methoxybenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) methyl 7-(4-methoxybenzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 298.0.

B) methyl7-(4-methoxybenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

MS: [M+H]⁺ 300.0.

C) 7-(4-methoxybenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylic acid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 286.1.

D)N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-methoxybenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 14N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) (4-(5-methyl-1,3-thiazol-2-yl)phenyl)methanol

The title compound was obtained from (4-(hydroxymethyl)phenyl)boronicacid and 2-bromo-5-methyl-1,3-thiazole by a method similar to that instep F of Example 1.

MS: [M+H]⁺ 206.1.

B) 2-(4-(chloromethyl)phenyl)-5-methyl-1,3-thiazole

To a mixture of (4-(5-methyl-1,3-thiazol-2-yl)phenyl)methanol (3.3 g)and DCM (120 mL) was added thionyl chloride (3.83 g) at 0° C. Afterstirring at room temperature for 3 hr, saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and the mixture wasextracted with DCM. The organic layer was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (2.8 g).

MS: [M+H]⁺ 224.1.

C) methyl7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 365.0.

D) methyl7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

MS: [M+H]⁺ 367.1.

E)7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 353.0.

F)N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(5-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 16N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) (4-(4-methyl-1,3-thiazol-2-yl)phenyl)methanol

The title compound was obtained from (4-(hydroxymethyl)phenyl)boronicacid and 2-bromo-4-methyl-1,3-thiazole by a method similar to that instep F of Example 1.

MS: [M+H]⁺ 206.1.

B) 2-(4-(chloromethyl)phenyl)-4-methyl-1,3-thiazole

The title compound was obtained by a method similar to that in step B ofExample 14.

MS: [M+H]⁺ 224.1.

C) methyl7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 365.0.

D) methyl7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

MS: [M+H]⁺ 367.0.

E)7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 353.1.

F)N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(4-methyl-1,3-thiazol-2-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 18N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) methyl 4-(2-methyl-1,3-thiazol-5-yl)benzoate

A mixture of methyl 4-iodobenzoate (1.75 g), 2-methyl-1,3-thiazole (0.99g), potassium acetate (1.96 g), Pd(PPh₃)₄ (35 mg) and DMA (60 mL) wasstirred at 100° C. overnight. After cooling to room temperature, waterwas added, and the mixture was extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/DCM) to give the title compound (500 mg).

MS: [M+H]⁺ 234.1.

B) (4-(2-methyl-1,3-thiazol-5-yl)phenyl)methanol

To a mixture of methyl 4-(2-methyl-1,3-thiazol-5-yl)benzoate (450 mg)and THF (30 mL) was added LAH (147 mg) at 0° C., and the mixture wasstirred at room temperature for 2 hr. Water (0.15 mL), 30% aqueoussodium hydroxide solution (0.15 mL) and water (0.45 mL) weresuccessively added dropwise to the mixture. The insoluble material wasfiltered off, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (330 mg).

MS: [M+H]⁺ 206.1.

C) 5-(4-(chloromethyl)phenyl)-2-methyl-1,3-thiazole

The title compound was obtained by a method similar to that in step B ofExample 14.

MS: [M+H]⁺ 224.1.

D) methyl7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 365.1.

E) methyl7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

MS: [M+H]⁺ 367.1.

F)7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 353.1.

G)N-((1S,2S)-2-hydroxycyclohexyl)-7-(4-(2-methyl-1,3-thiazol-5-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 201,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxamideA) 5-hydroxy-6-iodopyridine-2-carboxylic acid

To a mixture of 5-hydroxypyridine-2-carboxylic acid (10.0 g), sodiumcarbonate (15.68 g), potassium iodide (17.54 g) and water (100 mL) wasadded iodine (17.88 g) at 0° C. The mixture was stirred at 0° C. for 3hr, the reaction temperature was raised to room temperature, and themixture was stirred at room temperature overnight. To the mixture wasadded citric acid monohydrate (32.6 g) at room temperature, and themixture was stirred at room temperature for 1 hr. The precipitated solidwas collected by filtration to give the title compound (13.1 g)

MS: [M+H]⁺ 266.0.

B) methyl 5-hydroxy-6-iodopyridine-2-carboxylate

To a mixture of 5-hydroxy-6-iodopyridine-2-carboxylic acid (20.0 g) andMeOH (100 mL) was added concentrated sulfuric acid (8.05 mL) at roomtemperature. The mixture was stirred at 50° C. for 3 hr, and a solutionof sodium citrate (39.0 g) in water (100 mL) was added dropwise at 0° C.The precipitated solid was collected by filtration and washed with waterto give the title compound (17.7 g).

MS: [M+H]⁺ 280.0.

C) methyl 2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl 5-hydroxy-6-iodopyridine-2-carboxylate (10.0 g),TEA (36.3 g) and ethyl acetate (150 mL) were added PdCl₂(dppf) (1.31 g)and copper(I) iodide (0.341 g) at room temperature. The mixture wasstirred under an argon atmosphere at 15° C. for 5 min. While theinternal temperature was maintained at 15-18° C., to the mixture wasadded dropwise trimethylsilylacetylene (9.93 mL), and the mixture wasstirred at room temperature overnight. The insoluble material wasfiltered off, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (6.0 g).

MS: [M+H]⁺ 250.1.

D) methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of bis(1,5-cyclooctadiene)di-p-methoxydiiridium(I) (0.052g), 4,4′-di-tert-butyl-2,2′-bipyridine (0.042 g) and tert-butyl methylether (40 mL) was added bis(pinacolato)diboron (4.17 g), and the mixturewas stirred under an argon atmosphere at room temperature for 5 min. Tothe mixture was added methyl2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate (3.90 g), and themixture was stirred at 80° C. for 4 hr. After cooling the reactionmixture to room temperature, the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (5.87 g).

¹H NMR (300 MHz, CDCl₃) δ 0.40 (9H, s), 1.42 (12H, s), 4.03 (3H, s),7.23 (1H, s), 8.41 (1H, s).

E) methyl7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate(5.87 g), 4-(4-(bromomethyl)phenyl)-1-methyl-1H-1,2,3-triazole (4.13 g),PdCl₂(dppf) (0.114 g), sodium carbonate (2.486 g), DME (50 mL) and water(10 mL) was stirred under an argon atmosphere at 80° C. for 1 hr. Aftercooling the reaction mixture to room temperature, water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (4.2 g).

MS: [M+H]⁺ 421.1.

F) methyl7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

To a solution of methyl7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate(4.2 g) in MeOH (50 mL) was added potassium fluoride (0.87 g) at roomtemperature, and the mixture was stirred at 80° C. for 4 hr. Water (100mL) was added to the reaction mixture under stirring at roomtemperature. The precipitated solid was collected by filtration, washedwith water and IPE, and dried under reduced pressure to give the titlecompound (3.14 g).

MS: [M+H]⁺ 349.2.

G)7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

To a mixture of methyl7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate(13.6 g), water (180 mL) and MeOH (30 mL) was added 2 M aqueous sodiumhydroxide solution (39.0 mL) at room temperature. After stirring at 60°C. for 1 hr, the reaction mixture was filtered through celite to removethe insoluble material. To the filtrate were added water (80 mL) and 2 Mhydrochloric acid (50 mL). The mixture was stirred at room temperaturefor 30 min, and the precipitated solid was collected by filtration. Thesolid was washed with water and dried under reduced pressure to give thetitle compound (13.30 g).

MS: [M+H]⁺ 335.1.

H)1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)7-(4-(1H-pyrazol-1-yl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

To a mixture of7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid (14.1 g), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride(7.13 g), TEA (8.82 mL) and EtOH (200 mL) was added DMT-MM (20.36 g) atroom temperature. After stirring at room temperature for 3 hr, water wasadded to the mixture. The precipitated solid was collected byfiltration, washed with water (20 mL), and dried under reduced pressureto give the title compound (14.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.64 (1H, qd, J=12.1, 4.5 Hz), 1.84 (1H, dd,J=13.0, 4.3 Hz), 3.03 (1H, t, J=10.4 Hz), 3.26-3.41 (1H, m), 3.59 (1H,tt, J=9.8, 5.1 Hz), 3.72-3.89 (3H, m), 4.07 (3H, s), 4.37 (2H, s), 4.96(1H, d, J=5.7 Hz), 7.23 (1H, d, J=2.3 Hz), 7.39 (2H, d, J=8.3 Hz), 7.78(2H, d, J=8.3 Hz), 7.92 (1H, s), 8.43-8.50 (2H, m), 8.55 (1H, d, J=8.3Hz).

Example 221,5-anhydro-2,3-dideoxy-3-(((7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)7-(4-(1H-pyrazol-1-yl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

A mixture of7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid (106 mg), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride(60.8 mg), HATU (163 mg), TEA (0.115 mL) and DMF (3.0 mL) was stirred atroom temperature overnight. To the reaction mixture was added 5% aqueoussodium hydrogen carbonate solution at room temperature. The mixture wasextracted with ethyl acetate, and the organic layer was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (75mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.59 (1H, qd, J=12.3, 4.7 Hz), 1.81 (1H, dd,J=13.0, 4.3 Hz), 3.01 (1H, t, J=10.4 Hz), 3.25-3.40 (3H, m), 3.46-3.61(1H, m), 3.66-3.85 (3H, m), 3.97 (2H, s), 4.76 (2H, t, J=8.9 Hz), 4.92(1H, d, J=5.7 Hz), 6.48-6.56 (1H, m), 7.36 (2H, d, J=8.7 Hz), 7.65-7.80(4H, m), 8.25 (1H, d, J=8.3 Hz), 8.44 (1H, d, J=2.3 Hz).

Example 25N-(trans-5,5-difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 26N-(trans-5,5-difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide(Optical Isomer: Retention Time Short)

N-(trans-5,5-Difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide(71 mg) obtained in Example 25 was optically resolved by HPLC (CHIRALPAKAD, 50 mmID×500 mmL, mobile phase: hexane/EtOH=200/800), and thematerial having a shorter retention time (tR1) was triturated with ethylacetate-IPE to give the title compound (30 mg).

Example 27N-(trans-5,5-difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide(Optical Isomer: Retention Time Long)

N-(trans-5,5-Difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide(71 mg) obtained in Example 25 was optically resolved by HPLC (CHIRALPAKAD, 50 mmID×500 mmL, mobile phase: hexane/EtOH=200/800), and thematerial having a longer retention time (tR2) was triturated with ethylacetate-IPE to give the title compound (33 mg).

Example 291,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) 6-(1-methyl-1H-pyrazol-3-yl)nicotinaldehyde

The title compound was obtained from 6-chloronicotinaldehyde and1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole bya method similar to that in step F of Example 1.

¹H NMR (400 MHz, CDCl₃) δ 4.01 (3H, s), 6.97 (1H, d, J=2.45 Hz), 7.45(1H, d, J=2.45 Hz), 8.08 (1H, d, J=8.4 Hz), 8.19 (1H, dd, J=8.31, 1.96Hz), 9.05 (1H, d, J=1.47 Hz), 10.09 (1H, s).

B) (6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol

To a mixture of 6-(1-methyl-1H-pyrazol-3-yl)nicotinaldehyde (25.0 g) andMeOH (375 mL) was added sodium borohydride (10.16 g) at 0° C., and themixture was stirred at room temperature for 16 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (18.0g).

¹H NMR (500 MHz, CDCl₃) δ1.81 (1H, brs), 3.98 (3H, s), 4.74 (2H, d,J=4.88 Hz), 6.85 (1H, d, J=2.44 Hz), 7.41 (1H, d, J=2.44 Hz), 7.74 (1H,dd, J=8.09, 2.29 Hz), 7.90 (1H, d, J=7.93 Hz), 8.59 (1H, d, J=1.83 Hz).

C) 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridine

To a mixture of (6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol (18.0g), TEA (11.16 mL) and DCM (270 mL) was added dropwise methanesulfonylchloride (7.3 mL) at 0° C. The mixture was stirred at room temperaturefor 16 hr, water was added, and the mixture was extracted with DCM. Theorganic layer was washed with saturated brine and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (13.0 g).

¹H NMR (500 MHz, CDCl₃) δ 3.98 (3H, s), 4.61 (2H, s), 6.86 (1H, d,J=2.44 Hz), 7.41 (1H, d, J=2.14 Hz), 7.75 (1H, dd, J=8.09, 2.29 Hz),7.91 (1H, d, J=8.24 Hz), 8.60 (1H, d, J=2.14 Hz).

D) methyl7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 349.1.

E) methyl7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

MS: [M+H]⁺ 351.1.

F)7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 337.1.

G)1,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 311,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) methyl7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate(1.92 g), 10% palladium-carbon (NX type, 50% wet with water, 400 mg) andMeOH (400 mL) was stirred under a hydrogen atmosphere of 5 MPa at 50° C.for 3 hr. The catalyst was filtered off, and the filtrate wasconcentrated under reduced pressure. A mixture of the residue, 10%palladium-carbon (NX type, 50% wet with water, 400 mg) and MeOH (400 mL)was stirred under a hydrogen atmosphere of 5 MPa at 50° C. for 2 hr. Thecatalyst was filtered off, and the filtrate was concentrated to give thetitle compound (1.90 g)

MS: [M+H]⁺ 351.2.

B)7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

To a mixture of methyl7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate(2.72 g), MeOH (27 mL) and THF (13 mL) was added 2 M aqueous sodiumhydroxide solution (23.29 mL) at room temperature. After stirring atroom temperature overnight, 1 M hydrochloric acid (55 mL) was added, andthe precipitated solid was collected by filtration to give the titlecompound (2.31 g).

MS: [M+H]⁺ 337.2.

C)1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

To a mixture of7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid (350 mg), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride(192 mg), WSC.HCl (299 mg), HOBt.H₂O (191 mg) and DMF (7.0 mL) was addedTEA (0.653 mL) at room temperature. After stirring at room temperatureovernight, water was added to the reaction mixture. The precipitatedsolid was collected by filtration and washed with water. The solid wasrecrystallized from MEK/heptane to give the title compound (277 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.49-1.69 (1H, m), 1.75-1.87 (1H, m), 3.00(1H, t, J=10.4 Hz), 3.34-3.40 (3H, m), 3.54 (1H, tt, J=9.8, 5.1 Hz),3.67-3.85 (3H, m), 3.95 (2H, s), 4.08 (3H, s), 4.76 (2H, t, J=8.9 Hz),4.92 (1H, d, J=5.7 Hz), 7.31 (2H, d, J=8.3 Hz), 7.67 (1H, s), 7.76 (2H,d, J=8.3 Hz), 8.26 (1H, d, J=8.3 Hz), 8.46 (1H, s).

Example 33N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxamideA) methyl7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 350.1.

B)7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 336.1.

C)N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

¹H NMR (300 MHz, CDCl₃) δ 1.18-1.51 (4H, m), 1.78 (2H, d, J=7.9 Hz),2.01-2.23 (2H, m), 3.44-3.59 (2H, m), 3.85 (1H, brs.), 4.15 (3H, s),4.31 (2H, s), 6.99 (1H, d, J=2.3 Hz), 7.67 (1H, dd, J=8.1, 2.1 Hz), 7.93(1H, d, J=2.3 Hz), 8.01-8.13 (4H, m), 8.56 (1H, d, J=1.9 Hz).

Example 35N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxamideA) methyl7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate(800 mg), 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (603mg), sodium carbonate (559 mg), DME (13 mL) and water (4.0 mL) was addedPdCl₂(dppf) (97 mg) at room temperature, and the mixture was stirredunder an argon atmosphere at 80° C. for 1 hr. To the mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (543.6 mg).

MS: [M+H]⁺ 349.1.

B)7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylicacid

To a mixture of methyl7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate(150 mg), MeOH (3.0 mL) and THF (1.0 mL) was added 2 M aqueous sodiumhydroxide solution (1.0 mL) at room temperature. After stirring at roomtemperature for 19 hr, the solvent was evaporated under reducedpressure. To the residue was added water (6.0 mL), and the mixture wasneutralized with 1 M hydrochloric acid (2.0 mL). The mixture was stirredat room temperature for 3 hr, and the precipitated solid was collectedby filtration to give the title compound (143 mg).

MS: [M+H]⁺ 335.1.

C)N-((1S,2S)-2-hydroxycyclohexyl)-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 361,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxamide

To a mixture of7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylicacid (50 mg), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride(27.6 mg), WSC.HCl (43 mg), HOBt.H₂O (27.5 mg) and DMF (1.0 mL) wasadded TEA (0.073 mL), and the mixture was stirred at room temperaturefor 22 hr. To the mixture was added ethyl acetate. The mixture waswashed with water and saturated brine and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theprecipitate was washed with IPE and dried under reduced pressure to givethe title compound (32.5 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.74-1.92 (1H, m), 2.06 (1H, s), 3.23 (1H, dd,J=11.3, 9.8 Hz), 3.42-3.53 (1H, m), 3.65 (1H, td, J=9.1, 4.2 Hz),3.91-4.17 (6H, m), 4.25-4.32 (3H, m), 6.99 (1H, d, J=2.6 Hz), 7.37 (1H,d, J=8.7 Hz), 7.55 (1H, dd, J=8.1, 2.5 Hz), 7.89 (2H, d, J=6.8 Hz), 7.94(1H, d, J=2.3 Hz), 8.07 (1H, s), 8.14 (1H, d, J=7.2 Hz), 8.54 (1H, d,J=2.6 Hz).

Example 371,5-anhydro-2,3-dideoxy-3-(((7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) 7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 285.1.

B)1,5-anhydro-2,3-dideoxy-3-(((7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 381,5-anhydro-2,3-dideoxy-3-(((7-((6-oxo-1,6-dihydropyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

To a mixture of1,5-anhydro-2,3-dideoxy-3-(((7-((6-methoxypyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(115.8 mg) and acetonitrile (3.0 mL) were added sodium iodide (91 mg)and trimethylchlorosilane (0.116 mL) at room temperature. The mixturewas stirred at 80° C. for 1.5 hr and concentrated under reducedpressure. To the residue was added water, and the precipitated solid wascollected by filtration. The solid was washed with water and dried togive the title compound (109 mg).

Example 391,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl7-(hydroxy(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate(346.8 mg) and benzotrifluoride (7.0 mL) were added NBS (177 mg) andAIBN (32.7 mg) at room temperature. Under a nitrogen atmosphere, thereaction mixture was stirred under irradiation with a 60 W lamp at 80°C. for 1 hr. The reaction mixture was concentrated under reducedpressure, acetone (6.0 mL) and water (3.0 mL) were added to the residue,and the mixture was stirred at 50° C. for 5 hr. After ethyl acetate wasadded to the mixture, the mixture was added to water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, MeOH/ethyl acetate) to give the titlecompound (65.8 mg).

MS: [M+H]⁺ 365.1.

B) methyl7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-(hydroxy(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylate(65 mg) and THF (5.0 mL) was added DAST (0.03 mL) at 0° C., and themixture was stirred at room temperature for 0.5 hr and then at 60° C.for 0.5 hr. To the mixture was added DAST (0.03 mL) at 60° C., andmixture was stirred at the same temperature for 10 min. To the mixturewas added ethyl acetate, and the mixture was added to saturated aqueoussodium hydrogen carbonate. The organic layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (NH, ethyl acetate/hexane) to give thetitle compound (22.7 mg).

MS: [M+H]⁺ 367.1.

C)1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in steps Hand I of Example 1.

Example 401,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate(1000 mg), 4-(4-(chloromethyl)phenyl)-1-methyl-1H-pyrazole (750 mg),potassium carbonate (699 mg), DME (15 mL) and water (5.0 mL) was addedPdCl₂(dppf) (121 mg) at room temperature. The mixture was stirred underan argon atmosphere at 80° C. for 1 hr. The mixture was diluted withethyl acetate at room temperature and added to water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (729.0 mg).

MS: [M+H]⁺ 348.2.

B)7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

To a mixture of methyl7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate(294.2 mg), MeOH (6.0 mL) and THF (3.0 mL) was added 2 M aqueous sodiumhydroxide solution (2.0 mL) at room temperature. The mixture was stirredat room temperature for 3 hr, and the solvent was evaporated underreduced pressure. To the residue was added water (8.0 mL), and themixture was neutralized with 1 M hydrochloric acid (4.0 mL). Theprecipitated solid was collected by filtration, washed with water, anddried under reduced pressure to give the title compound (306 mg).

MS: [M+H]⁺ 334.1.

C)1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 42N-(trans-4,4-difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 431,5-anhydro-2,3-dideoxy-3-(((7-(4-(6-methylpyridazin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl7-(4-(6-methylpyridazin-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 360.1.

B) 7-(4-(6-methylpyridazin-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

¹H NMR (300 MHz, DMSO-d₆) 52.66 (3H, s), 4.42 (2H, s), 7.26 (1H, d,J=2.3 Hz), 7.52 (2H, d, J=8.3 Hz), 7.81-7.91 (3H, m), 7.94 (1H, s), 8.48(1H, d, J=2.6 Hz), 9.44 (1H, d, J=2.3 Hz), 13.12 (1H, brs.).

C)1,5-anhydro-2,3-dideoxy-3-(((7-(4-(6-methylpyridazin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 441,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) methyl7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate(466 mg), 10% palladium-carbon (50% wet with water, 93 mg) and MeOH (30ml) was stirred under a hydrogen atmosphere of 5 MPa at 50° C. for 6 hr.The catalyst was filtered off, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to give the title compound(389.1 mg).

MS: [M+H]⁺ 350.2.

B)7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

To a mixture of methyl7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate(389 mg), MeOH (8.0 mL) and THF (3.0 mL) was added 2 M aqueous sodiumhydroxide solution (3.0 mL) at room temperature. After stirring at roomtemperature for 4 hr, the mixture was concentrated under reducedpressure. To the residue was added water (12 mL), and the mixture wasneutralized with 1 M hydrochloric acid (6.0 mL). The precipitated solidwas collected by filtration, washed with water, and dried under reducedpressure to give the title compound (364 mg).

MS: [M+H]⁺ 336.1.

C)1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

To a mixture of7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid (55.9 mg), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride(51.2 mg), WSC.HCl (128 mg), HOBt.H₂O (51.1 mg) and DMF (1.0 mL) wasadded TEA (0.163 mL) at room temperature. After stirring at roomtemperature for 3 days, water was added to the mixture. The precipitatedsolid was collected by filtration, washed with water, and dried underreduced pressure to give the title compound (67.7 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.70-1.87 (1H, m), 1.93-2.08 (1H, m), 3.20(1H, dd, J=11.3, 9.8 Hz), 3.33 (2H, t, J=8.9 Hz), 3.45 (1H, td, J=11.9,2.3 Hz), 3.52-3.69 (1H, m), 3.81-4.03 (7H, m), 4.07 (1H, dd, J=11.3, 4.9Hz), 4.53 (1H, d, J=3.0 Hz), 4.76 (2H, t, J=9.1 Hz), 7.22 (2H, d, J=7.9Hz), 7.38 (2H, d, J=8.3 Hz), 7.57 (1H, s), 7.71 (1H, d, J=0.8 Hz), 7.85(1H, s), 7.90 (1H, d, J=5.7 Hz).

Example 45N-(trans-4,4-difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide(Optical Isomer: Retention Time Short)

N-(trans-4,4-Difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide(114 mg) produced in Example 42 was optically resolved by HPLC(CHIRALPAK IC, 50 mmID×500 mmL, mobile phase: hexane/EtOH=400/600), andthe material having a shorter retention time (tR1) was triturated withIPE to give the title compound (49.1 mg).

Example 46N-(trans-4,4-difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide(Optical Isomer: Retention Time Long)

N-(trans-4,4-Difluoro-2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide(114 mg) produced in Example 42 was optically resolved by HPLC(CHIRALPAK IC, 50 mmID×500 mmL, mobile phase: hexane/EtOH=400/600), andthe material having a longer retention time (tR2) was triturated withIPE to give the title compound (52.0 mg).

Example 491,5-anhydro-2,3-dideoxy-3-(((7-(4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) (4-(2-methylpyrimidin-4-yl)phenyl)methanol

The title compound was obtained from (4-(hydroxymethyl)phenyl)boronicacid and 4-chloro-2-methylpyrimidine by a method similar to that in stepF of Example 1.

MS: [M+H]⁺ 201.1.

B) 4-(4-(chloromethyl)phenyl)-2-methylpyrimidine

The title compound was obtained by a method similar to that in step B ofExample 14.

MS: [M+H]⁺ 219.1.

C) methyl7-(4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 360.2.

D) 7-(4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 346.2.

E)1,5-anhydro-2,3-dideoxy-3-(((7-(4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 511,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(Stereoisomer: Retention Time Short)

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(21.1 mg) produced in Example 39 was resolved by HPLC (CHIRALCEL OJ, 50mmID×500 mmL, mobile phase: hexane/EtOH=150/850), and the materialhaving a shorter retention time (tR1) was triturated with IPE to givethe title compound (3.1 mg).

Example 521,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(Stereoisomer: Retention Time Long)

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(21.1 mg) produced in Example 39 was resolved by HPLC (CHIRALCEL OJ, 50mmID×500 mmL, mobile phase: hexane/EtOH=150/850), and the materialhaving a longer retention time (tR2) was triturated with IPE to give thetitle compound (3.7 mg).

Example 531,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl7-(hydroxy(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylate(100 mg) and trifluorotoluene (3.0 mL) were added NBS (53.6 mg) and AIBN(4.71 mg) at room temperature. The mixture was stirred under a nitrogenatmosphere at 80° C. for 5 hr. After concentration under reducedpressure, acetone (3.0 mL) and water (10 mL) were added to the residue,and the mixture was stirred at 50° C. for 16 hr. The mixture was addedto water at room temperature, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (55.1 mg).

MS: [M+H]⁺ 365.2.

B) methyl7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-(hydroxy(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylate(212.6 mg) and dehydrated THF (12 mL) was added DAST (0.154 mL) at roomtemperature. After stirring the mixture at room temperature for 15 min,the mixture was added to saturated aqueous sodium hydrogen carbonate,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The precipitate wascollected by filtration, washed with IPE, and dried under reducedpressure to give the title compound (185 mg).

MS: [M+H]⁺ 367.2.

C) 7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylicacid

To a mixture of methyl7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylate(236 mg), MeOH (5.0 mL) and THF (3.0 mL) was added 2 M aqueous sodiumhydroxide solution (2.0 mL) at room temperature. The mixture was stirredat room temperature for 1 hr and concentrated under reduced pressure. Tothe residue was added water (6.0 mL), and the mixture was neutralizedwith 1 M hydrochloric acid (4.0 mL). The precipitated solid wascollected by filtration, washed with water, and dried under reducedpressure to give the title compound (219 mg).

MS: [M+H]⁺ 353.2.

D)1,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

To a mixture of7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridine-5-carboxylicacid (160 mg), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol (91 mg), WSC.HCl(174 mg), HOBt.H₂O (90 mg) and DMF (3.0 mL) was added TEA (0.253 mL) atroom temperature. The mixture was stirred at room temperature for 18 hr.The reaction mixture was added to water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. To the residue was added IPE, and theprecipitated solid was collected by filtration. The solid was washedwith IPE and dried under reduced pressure to give the title compound(200.6 mg).

Example 547-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)furo[3,2-b]pyridine-5-carboxamide

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 551,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(Stereoisomer: Retention Time Short) (synonym)7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)furo[3,2-b]pyridine-5-carboxamide(Stereoisomer: Retention Time Short)

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(194.6 mg) produced in Example 53 was resolved by HPLC (CHIRALPAK IA, 50mmID×500 mmL, mobile phase: EtOH), and the material having a shorterretention time (tR1) was triturated with IPE to give the title compound(70 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.76-1.92 (1H, m), 2.03-2.14 (1H, m), 3.25(1H, dd, J=11.3, 9.9 Hz), 3.50 (1H, td, J=12.0, 2.5 Hz), 3.57-3.75 (1H,m), 3.95-4.06 (2H, m), 4.06-4.18 (4H, m), 4.23 (1H, dd, J=3.5, 0.6 Hz),6.84-7.05 (2H, m), 7.53 (2H, d, J=7.4 Hz), 7.75 (1H, s), 7.84 (2H, d,J=8.0 Hz), 7.94 (1H, d, J=2.3 Hz), 8.14 (1H, d, J=5.9 Hz), 8.38 (1H, d,J=1.8 Hz).

Example 561,5-anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(Stereoisomer: Retention Time Long)

1,5-Anhydro-2,3-dideoxy-3-(((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(194.6 mg) produced in Example 53 was resolved by HPLC (CHIRALPAK IA, 50mmID×500 mmL, mobile phase: EtOH), and the material having a longerretention time (tR2) was triturated with IPE to give the title compound(80.2 mg).

Example 577-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)furo[3,2-b]pyridine-5-carboxamide(Stereoisomer: Retention Time Short)

7-(Fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)furo[3,2-b]pyridine-5-carboxamide(63 mg) produced in Example 54 was resolved by HPLC (CHIRALPAK AD, 50mmID×500 mmL, mobile phase: EtOH), and the material having a shorterretention time (tR1) was triturated with IPE to give the title compound(20.9 mg).

Example 587-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)furo[3,2-b]pyridine-5-carboxamide(Stereoisomer: Retention Time Long)

7-(Fluoro(4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N-((1S,2S)-2-hydroxycyclohexyl)furo[3,2-b]pyridine-5-carboxamide(63 mg) produced in Example 54 was resolved by HPLC (CHIRALPAK AD, 50mmID×500 mmL, mobile phase: EtOH), and the material having a longerretention time (tR2) was triturated with IPE to give the title compound(23.0 mg).

Example 601,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

MS: [M+H]⁺ 351.2.

B)7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 337.1.

C)1,5-anhydro-2,3-dideoxy-3-(((7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 621,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl7-(3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 343.2.

B)7-(3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 329.1.

C)1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

Example 631,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl 2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step G ofExample 1.

¹H NMR (300 MHz, CDCl₃) δ 3.42 (2H, t, J=8.9 Hz), 3.98 (3H, s), 4.76(2H, t, J=8.9 Hz), 7.07 (1H, d, J=8.7 Hz), 7.97 (1H, d, J=8.3 Hz).

B) methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step D ofExample 20.

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (12H, s), 3.24-3.32 (2H, m), 3.83 (3H,s), 4.75 (2H, t, J=8.9 Hz), 7.98 (1H, s).

C) methyl7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step F ofExample 1.

MS: [M+H]⁺ 345.2.

D)7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 1.

MS: [M+H]⁺ 331.1.

E)1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step H ofExample 20.

¹H NMR (300 MHz, DMSO-d₆) δ 1.51-1.68 (1H, m), 1.75-1.86 (1H, m), 2.75(3H, d, J=4.5 Hz), 2.96-3.06 (1H, m), 3.32 (3H, s), 3.49-3.61 (1H, m),3.70-3.83 (3H, m), 3.99 (2H, s), 4.75 (2H, t, J=8.9 Hz), 4.92 (1H, d,J=5.7 Hz), 7.10-7.20 (2H, m), 7.55 (1H, t, J=7.7 Hz), 7.68 (1H, s),8.14-8.22 (1H, m), 8.26 (1H, d, J=8.3 Hz).

Example 641,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl 7-chloro-2-iodofuro[3,2-b]pyridine-5-carboxylate

To a solution of methyl7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate (9.0 g) inacetonitrile (450 mL) were added N-iodosuccinimide (71.55 g) andpotassium fluoride (7.38 g) at room temperature, and the mixture wasstirred at 50° C. for 4 hr. The reaction mixture was concentrated underreduced pressure, an aqueous solution of sodium thiosulfate was added tothe residue, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (8.0 g).

MS: [M+H]⁺ 338.05.

B) methyl 7-chloro-2-methylfuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl 7-chloro-2-iodofuro[3,2-b]pyridine-5-carboxylate(8.00 g), methylboronic acid (2.84 g), tripotassium phosphate (15.1 g),tricyclohexylphosphine (1.99 g), palladium(II) acetate (1.06 g) andtoluene (240 mL) was stirred under an argon atmosphere at 120° C. for 18hr. After cooling the reaction mixture to room temperature, water wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (3.10 g).

MS: [M+H]⁺ 225.9.

C) methyl2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of bis(pinacolato)diboron (5.84 g), methyl7-chloro-2-methylfuro[3,2-b]pyridine-5-carboxylate (2.60 g),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.550 g),potassium acetate (3.39 g) and 1,4-dioxane (78 mL) was added Pd₂(dba)₃(0.528 g) at room temperature. The mixture was stirred under an argonatmosphere at 80° C. for 2 hr and cooled to room temperature. Thereaction mixture was diluted with THF and heated at 60° C. The insolublematerial was removed by celite filtration. The filtrate wasconcentrated, and the obtained solid was washed with pentane to give thetitle compound (2.60 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (12H, s), 2.58 (3H, s), 3.90 (3H, s),6.91 (1H, s), 8.13 (1H, s).

D)2-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

A mixture of methyl2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate(428 mg), 4-(4-(chloromethyl)phenyl)-1-methyl-1H-1,2,3-triazole (278mg), Pd(PPh₃)₄ (35 mg), potassium carbonate (372 mg), 1,4-dioxane (12mL) and water (4.0 mL) was subjected to microwave irradiation at 110° C.for 1 hr. The solvent was concentrated under reduced pressure. Theresidue was washed with ethyl acetate, 1 M hydrochloric acid was addedto adjust pH to 2, and the mixture was stirred. The precipitated solidwas collected by filtration and purified by silica gel columnchromatography (MeOH/dichloromethane) to give the title compound (200mg).

MS: [M+H]⁺ 349.41.

E)1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

¹H NMR (500 MHz, DMSO-d₆) δ 1.62-1.65 (1H, m), 1.81-1.84 (1H, m), 2.57(3H, d, J=0.92 Hz), 3.02 (1H, t, J=10.5 Hz), 3.30-3.34 (1H, m),3.57-3.61 (1H, m), 3.76-3.82 (3H, m), 4.07 (3H, s), 4.32 (2H, s), 4.95(1H, d, J=5.80 Hz), 6.87 (1H, d, J=1.22 Hz), 7.38 (2H, d, J=8.24 Hz),7.77-7.80 (3H, m), 8.47 (1H, s), 8.51 (1H, d, J=8.54 Hz).

Example 651,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-methylfuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA)7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-methylfuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step D ofExample 64.

MS: [M+H]⁺ 343.33.

B)1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-methylfuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62-1.68 (1H, m), 1.76-1.84 (1H, m), 2.56(3H, s), 2.75 (3H, d, J=4.40 Hz), 3.02 (1H, t, J=10.51 Hz), 3.34-3.35(1H, m), 3.59 (1H, brs), 3.77-3.82 (3H, m), 4.35 (2H, s), 4.94 (1H,brs), 6.87 (1H, s), 7.19-7.28 (2H, m), 7.56 (1H, t, J=7.83 Hz), 7.79(1H, s), 8.18 (1H, brs), 8.51 (1H, d, J=8.31 Hz).

Example 661,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA)2-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step D ofExample 64.

MS: [M+H]⁺ 348.37.

B)1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

¹H NMR (500 MHz, DMSO-d₆) δ 1.62-1.67 (1H, m), 1.81-1.84 (1H, m), 2.57(3H, s), 3.02 (1H, t, J=10.53 Hz), 3.33-3.34 (1H, s), 3.55-3.61 (1H, m),3.75-3.82 (3H, m), 3.84 (3H, s), 4.27 (2H, s), 4.94 (1H, d, J=5.80 Hz),6.86 (1H, d, J=0.92 Hz), 7.29 (2H, d, J=8.24 Hz), 7.50 (2H, d, J=7.93Hz), 7.78 (1H, s), 7.80 (1H, s), 8.07 (1H, s), 8.49 (1H, d, J=8.24 Hz).

Example 671,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA)2-methyl-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step D ofExample 64.

MS: [M+H]⁺ 334.27.

B)1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

¹H NMR (500 MHz, DMSO-d₆) δ 1.62-1.65 (1H, m), 1.81-1.84 (1H, m), 2.57(3H, d, J=0.92 Hz), 3.02 (1H, t, J=10.53 Hz), 3.29-3.31 (1H, m),3.57-3.62 (1H, m), 3.75-3.82 (3H, m), 4.34 (2H, s), 4.94 (1H, d, J=5.80Hz), 6.52 (1H, dd, J=2.44, 1.83 Hz), 6.87 (1H, d, J=1.22 Hz), 7.43 (2H,d, J=9.0 Hz), 7.72 (1H, d, J=1.83 Hz), 7.77-7.80 (3H, m), 8.45 (1H, dd,J=2.44, 0.61 Hz), 8.51 (1H, d, J=8.54 Hz).

Example 681,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA)2-methyl-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step D ofExample 64.

MS: [M+H]⁺ 350.35.

B)1,5-anhydro-2,3-dideoxy-3-(((2-methyl-7-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step I ofExample 1.

¹H NMR (500 MHz, DMSO-d₆) δ 1.63-1.67 (1H, m), 1.81-1.84 (1H, m), 2.57(3H, s), 3.02 (1H, t, J=10.38 Hz), 3.35-3.37 (1H, m), 3.57-3.62 (1H, m),3.77-3.82 (3H, m), 4.10 (3H, s), 4.36 (2H, s), 4.94 (1H, d, J=5.80 Hz),6.88 (1H, d, J=0.92 Hz), 7.80 (1H, dd, J=8.24, 2.14 Hz), 7.83 (1H, s),7.97 (1H, d, J=7.93 Hz), 8.51-8.52 (2H, m), 8.62 (1H, d, J=1.83 Hz).

Example 741,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) (4-(1-methyl-1H-imidazol-4-yl)phenyl)methanol

To a mixture of 4-bromo-1-methyl-1H-imidazole (25 g),(4-(hydroxymethyl)phenyl)boronic acid (47.2 g), DME (250 mL) and water(50 mL) were added cesium carbonate (100.93 g) and PdCl₂(dppf).DCM (6.33g) under an argon atmosphere at room temperature, and the mixture wasstirred under an argon atmosphere at 120° C. for 6 hr. The reactionmixture was diluted with ethyl acetate, and the insoluble material wasremoved by celite filtration. The filtrate was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate) to give the title compound (18.0 g).

MS: [M+H]⁺ 189.1.

B) 4-(4-(chloromethyl)phenyl)-1-methyl-1H-imidazole

To a mixture of (4-(1-methyl-1H-imidazol-4-yl)phenyl)methanol (15 g),DMF (2.5 mL) and DCM (400 mL) was added thionyl chloride (17.36 mL)under ice-cooling, and the mixture was stirred at room temperature for 2hr. The reaction mixture was concentrated, saturated aqueous sodiumhydrogen carbonate solution was added, and the mixture was extractedwith DCM. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound (11 g).

MS: M+H 207.06.

C)7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

A mixture of methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate(400 mg), 4-(4-(chloromethyl)phenyl)-1-methyl-1H-imidazole (325 mg),Pd(PPh₃)₄ (76 mg), potassium carbonate (725 mg), DME (7.5 mL) and water(4.5 mL) was subjected to microwave irradiation at 150° C. for 30 min.The reaction mixture was diluted by adding ethyl acetate and water, andthe mixture was extracted with 1 M sodium hydroxide. The obtainedaqueous layer was neutralized by adding 1 M hydrochloric acid. Theprecipitated solid was collected by filtration and dried under reducedpressure to give the title compound (164.2 mg).

MS: [M+H]⁺ 336.1.

D)1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

To a mixture of7-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid (100 mg), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride(55.0 mg), TEA (0.062 mL), HOBt (60.4 mg) and DMF (3.0 mL) was added WSC(0.078 mL) under ice-cooling. The mixture was stirred at roomtemperature overnight, and the solvent was evaporated under reducedpressure. To the residue was added water, and the mixture was extractedwith ethyl acetate. The organic layer was separated, washed withsaturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The obtained solid was crystallized from ethyl acetate/hexane to givethe title compound (81 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.59 (1H, qd, J=12.3, 4.5 Hz), 1.77-1.85(1H, m), 3.01 (1H, t, J=10.5 Hz), 3.24-3.39 (3H, m), 3.54 (1H, tt,J=9.8, 5.1 Hz), 3.67 (3H, s), 3.69-3.83 (3H, m), 3.90 (2H, s), 4.76 (2H,t, J=8.9 Hz), 4.93 (1H, d, J=5.4 Hz), 7.20 (2H, d, J=8.3 Hz), 7.54 (1H,d, J=1.2 Hz), 7.60 (1H, d, J=1.0 Hz), 7.63-7.68 (3H, m), 8.25 (1H, d,J=8.3 Hz).

Example 761,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamideA) tert-butyl 2-fluoro-4-methylbenzoate

A mixture of 2-fluoro-4-methylbenzoic acid (10 g) and toluene (160 mL)was stirred under an argon atmosphere at 80° C. for 30 min. A mixture of1,1-di-tert-butoxy-N,N-dimethylmethanamine (31.1 mL) and toluene (40 mL)was added dropwise at 80° C., and the mixture was stirred at 100° C. for2 hr. To the reaction mixture was added dropwise a mixture of1,1-di-tert-butoxy-N,N-dimethylmethanamine (15.56 mL) and toluene (20mL) at 80° C., and the mixture was stirred at 100° C. for 2 hr. Thereaction mixture was purified by silica gel column chromatography (NH,ethyl acetate) to give the title compound (11.19 g). The compound wasused in the next step without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ 1.53 (9H, s), 2.36 (3H, s), 7.06-7.20 (2H,m), 7.64-7.75 (1H, m).

B) tert-butyl 4-(bromomethyl)-2-fluorobenzoate

To a mixture of tert-butyl 2-fluoro-4-methylbenzoate (11.1 g), NBS (9.40g) and trifluorotoluene (140 mL) was added AIBN (0.867 g) at roomtemperature. The mixture was stirred under an argon atmosphere at 80° C.for 1 hr. The reaction mixture was cooled to room temperature andpartitioned between ethyl acetate and water. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (12.37 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.53-1.57 (9H, m), 4.73 (2H, s), 7.34-7.45(2H, m), 7.80 (1H, t, J=7.8 Hz).

C) methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate(9.56 g), 10% palladium-carbon (NX type, 50% wet with water, 1.92 g) andMeOH (300 mL) was stirred under a hydrogen atmosphere of 0.5-0.8 MPa at30° C. for 4 hr. To the reaction mixture was added THF (300 mL), and themixture was stirred under a hydrogen atmosphere of 0.5-0.8 MPa at roomtemperature overnight. The catalyst was filtered off, and the filtratewas concentrated under reduced pressure to give the title compound (9.52g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.23-1.36 (12H, m), 3.26-3.32 (2H, m), 3.83(3H, s), 4.72-4.79 (2H, m), 7.98 (1H, s).

D) methyl7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate(2.0 g), tert-butyl 4-(bromomethyl)-2-fluorobenzoate (2.09 g), Pd(PPh₃)₄(379 mg), potassium carbonate (3.62 g), DME (20 mL) and water (12 mL)was subjected to microwave irradiation at 70° C. for 10 min. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (1.96 g).

MS: [M+H]⁺ 388.2.

E)1,5-anhydro-3-(((7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

To a mixture of methyl7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate(1.1 g) and THF (10 mL) was added 1 M aqueous sodium hydroxide solution(5.68 mL) at room temperature, and the mixture was stirred at roomtemperature for 4 hr. After neutralization with 1 M hydrochloric acid,the reaction mixture was concentrated under reduced pressure to give7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid as a solid. A mixture of the obtained solid,(3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (0.567 mg), HATU(1.62 g), TEA (1.19 mL) and DMF (10 mL) was stirred at room temperaturefor 5 hr. To the reaction mixture was added water at room temperature,and the precipitated solid was collected by filtration and dried underreduced pressure to give the title compound (1.22 g).

MS: [M+H]⁺ 473.2.

F)1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

A mixture of1,5-anhydro-3-(((7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol(1.44 g) and 4 M hydrochloric acid-ethyl acetate solution (50 mL) wasstirred at room temperature for 3 hr. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspartitioned between ethyl acetate-1 M sodium hydroxide. The aqueouslayer was neutralized by adding 1 M hydrochloric acid under ice-cooling,and the precipitated solid was collected by filtration and dried underreduced pressure to give the title compound (1.12 g).

MS: [M+H]⁺ 417.2.

G)1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

To a mixture of1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol(1.1 g), 2-methoxyethanamine (0.344 mL), HOBt (535 mg) and DMF (30 mL)was added WSC (0.695 mL) at 0° C. After stirring at room temperatureovernight, the reaction mixture was concentrated under reduced pressure.The obtained residue was diluted with ethyl acetate, washed withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The obtained solid was recrystallized from ethylacetate/heptane to give the title compound (858 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.59 (1H, qd, J=12.3, 4.6 Hz), 1.81 (1H, dd,J=13.0, 4.4 Hz), 3.01 (1H, t, J=10.5 Hz), 3.26 (3H, s), 3.30-3.43 (7H,m), 3.54 (1H, tt, J=10.0, 5.0 Hz), 3.69-3.84 (3H, m), 3.99 (2H, s), 4.75(2H, t, J=8.8 Hz), 4.92 (1H, d, J=5.6 Hz), 7.07-7.21 (2H, m), 7.54 (1H,t, J=7.7 Hz), 7.69 (1H, s), 8.20-8.31 (2H, m).

Example 771,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)7-(3-fluoro-4-((((S)-tetrahydrofuran-2-yl)methyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

A mixture of1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol(100 mg), 1-((2S)-tetrahydrofuran-2-yl)methanamine (36.4 mg), WSC (0.085mL), HOBt.H₂O (73.6 mg), TEA (0.100 mL) and DMF (2.0 mL) was stirred atroom temperature overnight. To the reaction mixture was added saturatedbrine, and the mixture was extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane). The obtained solid wascrystallized from ethyl acetate/hexane to give the title compound (91mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.47-1.68 (2H, m), 1.69-1.95 (4H, m), 3.01(1H, t, J=10.5 Hz), 3.21-3.32 (3H, m), 3.33-3.40 (2H, m), 3.48-3.57 (1H,m), 3.58-3.65 (1H, m), 3.68-3.84 (4H, m), 3.89-3.96 (1H, m), 3.99 (2H,s), 4.75 (2H, t, J=8.9 Hz), 4.92 (1H, d, J=5.6 Hz), 7.09-7.24 (2H, m),7.53 (1H, t, J=7.8 Hz), 7.69 (1H, s), 8.16-8.36 (2H, m).

Example 95 methyl((2-fluoro-4-((5-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3-dihydrofuro[3,2-b]pyridin-7-yl)methyl)benzoyl)amino)acetate

A mixture of1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol(200 mg), glycine methyl ester hydrochloride (90 mg), WSC (112 mg), HOBt(97 mg), TEA (0.201 mL) and DMF (3.0 mL) was stirred at 50° C. for 3 hr.To the reaction mixture was added saturated brine, and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (NH, ethylacetate/hexane). The obtained solid was crystallized from ethylacetate/hexane to give the title compound (183 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.51-1.68 (1H, m), 1.75-1.86 (1H, m), 3.01(2H, t, J=10.5 Hz), 3.26-3.32 (1H, m), 3.33-3.39 (2H, m), 3.49-3.60 (1H,m), 3.68-3.86 (4H, m), 3.93-4.06 (5H, m), 4.75 (2H, t, J=8.9 Hz), 4.92(1H, d, J=5.9 Hz), 7.12-7.25 (2H, m), 7.61 (1H, t, J=7.8 Hz), 7.70 (1H,s), 8.27 (1H, d, J=8.1 Hz), 8.52-8.73 (1H, m).

Example 96((2-fluoro-4-((5-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3-dihydrofuro[3,2-b]pyridin-7-yl)methyl)benzoyl)amino)aceticacid

To a mixture of methyl2-(2-fluoro-4-((5-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3-dihydrofuro[3,2-b]pyridin-7-yl)methyl)benzamido)acetate(220 mg), MeOH (2.0 mL) and THF (2.0 mL) was added 1 M aqueous sodiumhydroxide solution (2.0 mL) at room temperature, and the mixture wasstirred at 50° C. for 1 hr. The reaction mixture was neutralized with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedsolid was crystallized from ethyl acetate/hexane to give the titlecompound (179 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.47-1.68 (1H, m), 1.74-1.86 (1H, m),2.94-3.08 (1H, m), 3.26-3.32 (1H, m), 3.33-3.39 (2H, m), 3.47-3.61 (1H,m), 3.67-3.84 (3H, m), 3.88-3.94 (2H, m), 4.01 (2H, s), 4.75 (2H, t,J=8.8 Hz), 4.92 (1H, d, J=5.6 Hz), 7.10-7.26 (2H, m), 7.62 (1H, t, J=7.8Hz), 7.70 (1H, s), 8.27 (1H, d, J=8.1 Hz), 8.39-8.55 (1H, m), 12.60 (1H,s).

Example 991,5-anhydro-2,3-dideoxy-3-(((7-(4-((2-(diethylamino)-2-oxoethyl)carbamoyl)-3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

A mixture of2-(2-fluoro-4-((5-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3-dihydrofuro[3,2-b]pyridin-7-yl)methyl)benzamido)aceticacid (50 mg), N-ethylethanamine (23.17 mg), WSC (49.2 mg), HOBt.H₂O(24.26 mg), TEA (0.044 mL) and DMF (2.0 mL) was stirred at roomtemperature overnight. To the reaction mixture was added HATU (80 mg),and the mixture was stirred at room temperature for 3 hr. To thereaction mixture was added saturated brine, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (18.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93-1.08 (3H, m), 1.09-1.22 (3H, m),1.45-1.68 (1H, m), 1.68-1.92 (1H, m), 2.94-3.08 (1H, m), 3.24-3.31 (4H,m), 3.33-3.39 (3H, m), 3.46-3.64 (1H, m), 3.69-3.86 (3H, m), 4.01 (2H,s), 4.11 (2H, d, J=5.3 Hz), 4.75 (2H, t, J=8.7 Hz), 4.92 (1H, d, J=6.0Hz), 7.07-7.28 (2H, m), 7.60-7.76 (2H, m), 8.11-8.23 (1H, m), 8.26 (1H,d, J=8.3 Hz).

Example 1021,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)7-(3-fluoro-4-((((S)-tetrahydrofuran-2-yl)methyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)furo[3,2-b]pyridine-5-carboxamideA) methyl7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate(2.6 g), tert-butyl 4-(bromomethyl)-2-fluorobenzoate (2.8 g), Pd(PPh₃)₄(466 mg), potassium carbonate (4.46 g), DME (12 mL) and water (2 mL) wassubjected to microwave irradiation at 80° C. for 20 min. To the reactionmixture was added saturated brine, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (2.30 g).

MS: [M+H]⁺ 386.2.

B)7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-carboxylicacid

To a mixture of methyl7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-carboxylate(1.63 g), THF (30 mL) and MeOH (30 mL) was added 1 M aqueous sodiumhydroxide solution (8.46 mL) at room temperature, and the mixture wasstirred at room temperature for 2 hr. The reaction mixture wasconcentrated under reduced pressure, ice water was added to the residue,and the mixture was washed with ethyl acetate. The aqueous layer wasneutralized by adding 1 M hydrochloric acid under ice-cooling andstirred for a while, and the precipitated solid was collected byfiltration to give the title compound (1.53 g).

MS: [M+H]⁺ 372.2.

C)1,5-anhydro-3-(((7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

To a mixture of7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridine-5-carboxylicacid (1.53 g), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride(759 mg), HOBt (835 mg) and DMF (20 mL) was added WSC (1.084 mL). Themixture was stirred at room temperature overnight. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was separated, washed with saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The obtained solid wascrystallized from ethyl acetate/ethanol to give the title compound (1.81g).

MS: [M+H]⁺ 471.3.

D)1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

A mixture of1,5-anhydro-3-(((7-(4-(tert-butoxycarbonyl)-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol(1.91 g) and 4 M hydrochloric acid-ethyl acetate solution (50 mL) wasstirred at room temperature for 3 hr. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspartitioned between ethyl acetate-1 M sodium hydroxide. The aqueouslayer was neutralized by adding 1 M hydrochloric acid under ice-cooling,and the precipitated solid was collected by filtration and dried underreduced pressure to give the title compound (1.32 g)

MS: [M+H]⁺ 415.2.

E)1,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)7-(3-fluoro-4-((((S)-tetrahydrofuran-2-yl)methyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)furo[3,2-b]pyridine-5-carboxamide

To a mixture of1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol(1.31 g), 1-((2S)-tetrahydrofuran-2-yl)methanamine (0.480 g), HOBt (641mg) and DMF (30 mL) was added WSC (0.832 mL) under ice-cooling. Themixture was stirred at room temperature overnight. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate/heptane to give the title compound (1.21g). ¹H NMR (400 MHz, DMSO-d₆) δ 1.49-1.71 (2H, m), 1.73-1.96 (4H, m),3.03 (1H, t, J=10.5 Hz), 3.19-3.40 (3H, m), 3.52-3.67 (2H, m), 3.70-3.85(4H, m), 3.93 (1H, quin, J=6.2 Hz), 4.41 (2H, s), 4.96 (1H, d, J=5.6Hz), 7.12-7.32 (3H, m), 7.54 (1H, t, J=7.8 Hz), 7.92 (1H, s), 8.16-8.35(1H, m), 8.47 (1H, d, J=2.4 Hz), 8.56 (1H, d, J=8.3 Hz).

Example 1091,5-anhydro-2,3-dideoxy-3-(((7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol(synonym)7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)furo[3,2-b]pyridine-5-carboxamide

A mixture of1,5-anhydro-3-(((7-(4-carboxy-3-fluorobenzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol(70 mg), 2-methoxyethanamine (38.1 mg), WSC (0.089 mL), HOBt.H₂O (51.7mg), TEA (0.071 mL) and DMF (2.0 mL) was stirred at room temperatureovernight. To the reaction mixture was added HATU (128 mg), and themixture was stirred at room temperature for 1 hr. To the reactionmixture was added saturated brine, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and the obtained solid was crystallized fromethyl acetate/hexane to give the title compound (31.3 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.55-1.70 (1H, m), 1.77-1.90 (1H, m), 3.03(1H, s), 3.23-3.27 (3H, m), 3.28-3.31 (1H, m), 3.35-3.47 (4H, m),3.51-3.68 (1H, m), 3.80 (3H, td, J=10.2, 4.3 Hz), 4.41 (2H, s), 4.96(1H, d, J=5.9 Hz), 7.17-7.24 (2H, m), 7.28 (1H, d, J=11.5 Hz), 7.55 (1H,t, J=7.8 Hz), 7.92 (1H, s), 8.19-8.31 (1H, m), 8.45-8.49 (1H, m),8.51-8.63 (1H, m).

Example 1111,5-anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) 1-(3-fluoro-4-(methoxymethoxy)phenyl)ethanone

A mixture of 1-(3-fluoro-4-hydroxyphenyl)ethanone (5.0 g),chloro(methoxy)methane (2.96 mL), potassium carbonate (5.38 g) and DMF(50 mL) was stirred at room temperature for 2 hr. To the reactionmixture was added saturated aqueous sodium hydrogen carbonate solutionat room temperature, and the mixture was extracted with ethyl acetate.The organic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (6.09 g).

MS: [M+H]⁺ 199.0.

B) methyl7-(1-(3-fluoro-4-(methoxymethoxy)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of 1-(3-fluoro-4-(methoxymethoxy)phenyl)ethanone (1.70 g),4-methylbenzenesulfonohydrazide (2.40 g) and toluene (34.3 mL) wasstirred at 80° C. for 2 hr. To the reaction mixture were added methyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine-5-carboxylate(3.12 g) and potassium carbonate (2.37 g), and the mixture was stirredat 110° C. for 4 hr. After cooling the reaction mixture to roomtemperature, saturated brine was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (1.6 g).

MS: [M+H]⁺ 360.0.

C) methyl7-(1-(3-fluoro-4-hydroxyphenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(1-(3-fluoro-4-(methoxymethoxy)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate(2.1 g) and 2 M hydrochloric acid methanol solution (4.26 g) was stirredat room temperature overnight. To the reaction mixture was addedsaturated brine at room temperature, and the mixture was extracted withethyl acetate. The organic layer was separated, washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to give the title compound (960 mg). The compound wasused in the next step without further purification.

MS: [M+H]⁺ 316.0.

D) methyl7-(1-(3-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate

To a mixture of methyl7-(1-(3-fluoro-4-hydroxyphenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate(860 mg) and pyridine (3 mL) was added trifluoromethanesulfonicanhydride (5.46 mL) under ice-cooling, and the mixture was stirred underice-cooling for 3 hr. To the reaction mixture was added saturated brine,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.01 g).

MS: [M+H]⁺ 448.0.

E) methyl7-(1-(3-fluoro-4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(1-(3-fluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate(1.01 g), 2-(trimethylsilyl)ethanol (0.971 mL), palladium(II) acetate(76 mg), 1,3-bis(diphenylphosphino)propane (140 mg), TEA (0.629 mL) andDMF (10 mL) was stirred under a carbon monoxide atmosphere at 70° C. for4 hr. The reaction mixture was concentrated, and the residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (801 mg).

MS: [M+H]⁺ 444.1.

F)2-fluoro-4-(1-(5-(methoxycarbonyl)furo[3,2-b]pyridin-7-yl)ethyl)benzoicacid

To a mixture of methyl7-(1-(3-fluoro-4-((2-(trimethylsilyl)ethoxy)carbonyl)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate(810 mg) and THF (20 mL) was added 1 M tetra-n-butylammonium fluorideTHF solution (3.65 mL) under ice-cooling, and the mixture was stirred atroom temperature for 3 hr. To the reaction mixture was added 1 Nhydrochloric acid at 0° C., and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The obtained solid was crystallized from ethyl acetate/hexaneto give the title compound (361 mg).

MS: [M+H]⁺ 344.0.

G) methyl7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate

A mixture of2-fluoro-4-(1-(5-(methoxycarbonyl)furo[3,2-b]pyridin-7-yl)ethyl)benzoicacid (300 mg), 2-methoxyethanamine (131 mg), HATU (665 mg), TEA (0.487mL) and DMF (3.0 mL) was stirred at room temperature for 2 hr. To thereaction mixture was added saturated brine, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (162 mg).

MS: [M+H]⁺ 401.1.

H)1,5-anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

To a mixture of methyl7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate(52 mg), MeOH (1 mL) and THF (1 mL) was added 4 M aqueous lithiumhydroxide solution (0.097 mL) at room temperature. After stirring atroom temperature for 2 hr, 6 M hydrochloric acid (0.065 mL) was added,and the mixture was concentrated to give7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylicacid as a solid. A mixture of the obtained solid,(3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (30 mg), HATU(74.1 mg), TEA (0.036 mL) and DMF (1.0 mL) was stirred at roomtemperature for 2 hr. To the reaction mixture was added saturated brine,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (52.0 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.59-1.69 (1H, m), 1.71-1.79 (3H, m),1.80-1.90 (1H, m), 2.95-3.11 (1H, m), 3.25 (3H, s), 3.33-3.44 (5H, m),3.52-3.67 (1H, m), 3.72-3.89 (3H, m), 4.80 (1H, q, J=7.1 Hz), 4.97 (1H,dd, J=5.5, 4.3 Hz), 7.16-7.26 (2H, m), 7.31 (1H, dd, J=11.7, 1.5 Hz),7.54 (1H, t, J=7.8 Hz), 7.98 (1H, s), 8.26 (1H, brs), 8.44 (1H, d, J=2.2Hz), 8.57 (1H, d, J=8.3 Hz).

Example 1121,5-anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) methyl7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

A mixture of methyl7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)furo[3,2-b]pyridine-5-carboxylate(160 mg), 10% palladium-carbon (NX type, 50% wet with water, 32 mg) andMeOH (30 mL) was stirred under a hydrogen atmosphere of 5 MPa at 50° C.for 4.5 hr. The catalyst was filtered off, and the filtrate wasconcentrated under reduced pressure to give the title compound (140 mg).The compound was used in the next step without further purification.

MS: [M+H]⁺ 403.2.

B)7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step H ofExample 111.

MS: [M+H]⁺ 389.1.

C)1,5-anhydro-2,3-dideoxy-3-(((7-(1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)ethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in step H ofExample 111.

¹H NMR (400 MHz, DMSO-d₆) δ 1.49-1.66 (4H, m), 1.75-1.85 (1H, m),2.94-3.07 (2H, m), 3.25 (3H, s), 3.28-3.31 (1H, m), 3.35-3.47 (5H, m),3.49-3.61 (1H, m), 3.68-3.87 (3H, m), 4.34 (1H, q, J=7.0 Hz), 4.72 (2H,t, J=9.0 Hz), 4.92 (1H, t, J=5.4 Hz), 7.08-7.30 (2H, m), 7.48-7.59 (1H,m), 7.72 (1H, s), 8.12-8.37 (2H, m).

Example 1131,5-anhydro-2,3-dideoxy-3-(((7-((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitolA) 2-methyl-1-oxoisoindoline-5-carbaldehyde

A mixture of 5-bromo-2-methylisoindolin-1-one (1030 mg),2-isocyano-2-methylpropane (947 mg), sodium carbonate (579 mg),palladium(II) acetate (102 mg), biphenyl-2-yl(di-tert-butyl)phosphine(272 mg), triethylsilane (2.18 mL) and DMF (20 mL) was stirred under anitrogen atmosphere at 75° C. for 2.5 hr. After cooling the reactionmixture to room temperature, water was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (MeOH/ethyl acetate) to give the titlecompound (690 mg).

MS: M+H 176.4.

B) 5-(hydroxymethyl)-2-methylisoindolin-1-one

To a mixture of 2-methyl-1-oxoisoindoline-5-carbaldehyde (660 mg) andTHF (20 mL) was added sodium borohydride (285 mg) at 0° C., and themixture was stirred at room temperature for 1 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate solvent, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(MeOH/ethyl acetate) to give the title compound (576 mg).

MS: [M+H]⁺ 178.4.

C) 5-(chloromethyl)-2-methylisoindolin-1-one

To a mixture of 5-(hydroxymethyl)-2-methylisoindolin-1-one (576 mg),toluene (5 mL) and acetonitrile (10 mL) was added thionyl chloride(0.475 mL) at 0° C. After stirring at room temperature for 1 hr, aqueoussodium hydrogen carbonate solution was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (MeOH/ethyl acetate) to give the titlecompound (126 mg).

MS: [M+H]⁺ 196.4.

D) methyl7-((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

The title compound was obtained by a method similar to that in step A ofExample 102.

MS: [M+H]⁺ 339.4.

E)7-((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylicacid

The title compound was obtained by a method similar to that in step B ofExample 31.

MS: [M+H]⁺ 325.3.

F)1,5-anhydro-2,3-dideoxy-3-(((7-((2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

The title compound was obtained by a method similar to that in Example22.

¹H NMR (400 MHz, DMSO-d₆) δ 1.59 (1H, qd, J=12.3, 4.4 Hz), 1.80 (1H, dd,J=13.2, 4.4 Hz), 2.98-3.05 (4H, m), 3.26-3.31 (1H, m), 3.33-3.38 (2H,m), 3.55 (1H, d, J=5.1 Hz), 3.77 (3H, td, J=10.8, 4.4 Hz), 4.04 (2H, s),4.42 (2H, s), 4.75 (2H, t, J=8.9 Hz), 4.92 (1H, d, J=5.6 Hz), 7.35 (1H,d, J=8.1 Hz), 7.43 (1H, s), 7.59 (1H, d, J=7.8 Hz), 7.67 (1H, s), 8.26(1H, d, J=8.1 Hz).

The compounds of Examples are shown in the following Tables. In theTables, MS means measured values. The compounds of Examples 2, 3, 6, 7,9, 11, 13, 15, 17, 19, 21, 23, 24, 28, 30, 32, 34, 41, 47, 48, 50, 59,61, 69-73, 75, 78-94, 97, 98, 100, 101, 103-108 and 110 in the followingTables were produced by the methods shown in the above-mentionedExamples or a method analogous thereto.

TABLE 1 Ex. No. IUPAC name structural formula salt MS 1 N-((1S,2S)-2-hydroxycyclopentyl)-7- (4-(1H-pyrazol-1- yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

405.2 2 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-(1H-pyrazol-1-yl)benzyl)-2,3- dihydrofuro[3,2- b]pyridine-5- carboxamide

419.2 3 1,5-anhydro-2,4- dideoxy-2-(((7-(4-(1H- pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

421.2 4 N-(1S,2S)-2- hydroxycyclohexyl)-7- (4-(1H-pyrazol-1-yl)benzyl)furo[3,2- b]pyridine-5- carboxamide

417.2 5 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-(1-methyl-1H- pyrazol-3-yl)benzyl)furo[3,2- b]pyridine-5- carboxamide

431.2 6 1,5-anhydro-2,4- dideoxy-2-(((7-(4-(1H- pyrazol-1-yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

419.1 7 1,5-anhydro-2,4- dideoxy-2-(((7-(4-(1- methyl-1H-pyrazol-3-yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

433.1 8 1,5-anhydro-2,4- dideoxy-2-(((7-(4-(1- methyl-1H-pyrazol-3-yl)benzyl)-2,3- dihydrofuro[3,2- b]pyridin-5- yl)carbonyl)amino)-L-threo-pentitol

435.2 9 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-(1-methyl-1H-pyrazol-3-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

433.2 10 N-((1S,2S)-2- hydroxycyclohexyl)-7- ((6-methoxypyridin-3-yl)methyl)-2,3- dihydrofuro[3,2- b]pyridine-5- carboxamide

384.3 11 N-((1S,2S)-2- hydroxycyclopentyl)-7- ((6-methoxypyridin-3-yl)methyl)-2,3- dihydrofuro[3,2- b]pyridine-5- carboxamide

370.3 12 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-methoxybenzyl)-2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

383.2 13 N-((1S,2S)-2- hydroxycyclopentyl)-7- (4-methoxybenzyl)-2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

369.2 14 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-(5-methyl-1,3-thiazol-2-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

450.2 15 N-((1S,2S)-2- hydroxycyclopentyl)-7- (4-(5-methyl-1,3-thiazol-2-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

436.2 16 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-(4-methyl-1,3-thiazol-2-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

450.2 17 N-((1S,2S)-2- hydroxycyclopentyl)-7- (4-(4-methyl-1,3-thiazol-2-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

436.2 18 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-(2-methyl-1,3-thiazol-5-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

450.2 19 N-((1S,2S)-2- hydroxycyclopentyl)-7- (4-(2-methyl-1,3-thiazol-5-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

436.2 20 1,5-anhydro-2,3-dideoxy-3-(((7- (4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridin- 5-yl)carbonyl)amino)-L-threo- pentitol(synonym) N-((3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-1,2,3- triazol-4-yl)benzyl)furo[3,2-b]pyridine-5-carboxamide

434.1 21 1,5-anhydro-2,4-dideoxy-2-(((7- (4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)furo[3,2-b]pyridin- 5-yl)carbonyl)amino)-L-threo- pentitol

434.1 22 1,5-anhydro-2,3-dideoxy-3-(((7- (4-(1H-pyrazol-1-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin- 5-yl)carbonyl)amino)-L-threo- pentitol(synonym) 7-(4-(1H-pyrazol-1- yl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4- yl)-2,3-dihydrofuro[3,2-b]pyridine-5-carboxamide

421.2 23 N-((1S,2S)-2- hydroxycyclohexyl)-7-(4-(1-methyl-1H-1,2,3-triazol-4- yl)benzyl)furo[3,2-b]pyridine- 5-carboxamide

432.2 24 N-(trans-5,5-difluoro-2- hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)furo[3,2- b]pyridine-5-carboxamide

453.2 25 N-(trans-5,5-difluoro-2- hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3- dihydrofuro[3,2-b]pyridine-5- carboxamide

455.2 26 N-(trans-5,5-difluoro-2- hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3- dihydrofuro[3,2-b]pyridine-5- carboxamide(optical isomer: retention time short)

455.2 27 N-(trans-5,5-difluoro-2- hydroxycyclohexyl)-7-(4-(1H-pyrazol-1-yl)benzyl)-2,3- dihydrofuro[3,2-b]pyridine-5- carboxamide(optical isomer: retention time long)

455.2 28 1,5-anhydro-2,3-dideoxy-3-(((7- (4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

435.2 29 1,5-anhydro-2,3- dideoxy-3-(((7-((6-(1- methyl-1H-pyrazol-3-yl)pyridin-3- yl)methyl)-2,3- dihydrofuro[3,2- b]pyridin-5-yl)carbonyl)amino)-L- threo-pentitol

436.2 30 N-(2- hydroxycyclobutyl)-7- (4-(1H-pyrazol-1- yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

391.2 31 1,5-anhydro-2,3- dideoxy-3-(((7-(4-(1- methyl-1H-1,2,3-triazol-4-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridin-5-yl)carbonyl)amino)-L- threo-pentitol (synonym) N-((3R,4S)-3-hydroxytetrahydro-2H- pyran-4-yl)-7-(4-(1- methyl-1H-1,2,3-triazol-4-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

436.2 32 N-((1S,2S)-2- hydroxycyclohexyl)-7- ((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3- yl)methyl)-2,3- dihydrofuro[3,2- b]pyridine-5-carboxamide

434.2 33 N-((1S,2S)-2- hydroxycyclohexyl)-7- ((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3- yl)methyl)furo[3,2- b]pyridine-5- carboxamide

433.2 34 1,5-anhydro-2,3- dideoxy-3-(((7-((6-(1- methyl-1H-1,2,3-triazol-4-yl)pyridin-3- yl)methyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L- threo-pentitol

435.2 35 N-((1S,2S)-2- hydroxycyclohexyl)-7- ((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)furo[3,2- b]pyridine-5- carboxamide

432.2 36 1,5-anhydro-2,3- dideoxy-3-(((7-((6-(1- methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L-threo-pentitol (synonym) N-((3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)-7-((6-(1- methyl-1H-pyrazol-4- yl)pyridin-3-yl)methyl)furo[3,2- b]pyridine-5- carboxamide

434.1 37 1,5-anhydro-2,3- dideoxy-3-(((7-((6- methoxypyridin-3-yl)methyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

384.2 38 1,5-anhydro-2,3- dideoxy-3-(((7-((6-oxo- 1,6-dihydropyridin-3-yl)methyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

370.2 39 1,5-anhydro-2,3- dideoxy-3-(((7- (fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L- threo-pentitol

452.2 40 1,5-anhydro-2,3- dideoxy-3-(((7-(4-(1- methyl-1H-pyrazol-4-yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

433.2 41 1,5-anhydro-2,4- dideoxy-2-(((7-(4-(1- methyl-1H-pyrazol-4-yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

433.2 42 N-(trans-4,4-difluoro- 2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1- yl)benzyl)-2,3- dihydrofuro[3,2- b]pyridine-5-carboxamide

455.2 43 1,5-anhydro-2,3- dideoxy-3-(((7-(4-(6- methylpyridazin-4-yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

445.2 44 1,5-anhydro-2,3- dideoxy-3-(((7-(4-(1- methyl-1H-pyrazol-4-yl)benzyl)-2,3- dihydrofuro[3,2- b]pyridin-5- yl)carbonyl)amino)-L-threo-pentitol (synonym) N-((3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1- methyl-1H-pyrazol-4- yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

435.2 45 N-(trans-4,4-difluoro- 2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1- yl)benzyl)-2,3- dihydrofuro[3,2- b]pyridine-5-carboxamide (optical isomer: retention time short)

455.2 46 N-(trans-4,4-difluoro- 2-hydroxycyclohexyl)-7-(4-(1H-pyrazol-1- yl)benzyl)-2,3- dihydrofuro[3,2- b]pyridine-5-carboxamide (optical isomer: retention time long)

455.2 47 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)- 2,3-dihydrofuro[3,2- b]pyridine-5- carboxamide

434.2 48 1,5-anhydro-2,3- dideoxy-3-(((7-(4-(1H- pyrazol-1-yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

419.2 49 1,5-anhydro-2,3- dideoxy-3-(((7-(4-(2- methylpyrimidin-4-yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

445.2 50 N-((1S,2S)-2- hydroxycyclohexyl)-7- (4-(2-methylpyrimidin-4-yl)benzyl)furo[3,2- b]pyridine-5- carboxamide

443.3 51 1,5-anhydro-2,3-dideoxy-3- (((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol (stereoisomer: retention timeshort)

452.2 52 1,5-anhydro-2,3-dideoxy-3- (((7-(fluoro(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3- yl)methyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol (stereoisomer: retention time long)

452.2 53 1,5-anhydro-2,3-dideoxy-3- (((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4- yl)phenyl)methyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

452.2 54 7-(fluoro(4-(1-methyl-1H- 1,2,3-triazol-4- yl)phenyl)methyl)-N-((1S,2S)-2- hydroxycyclohexyl)furo[3,2- b]pyridine-5-carboxamide

450.2 55 1,5-anhydro-2,3-dideoxy-3- (((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4- yl)phenyl)methyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol (stereoisomer: retention timeshort) (synonym) 7-(fluoro(4-(1- methyl-1H-1,2,3-triazol-4-yl)phenyl)methyl)-N- ((3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)furo[3,2-b]pyridine-5- carboxamide (stereoisomer: retention timeshort)

452.2 56 1,5-anhydro-2,3-dideoxy-3- (((7-(fluoro(4-(1-methyl-1H-1,2,3-triazol-4- yl)phenyl)methyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol (stereoisomer: retention time long)

452.2 57 7-(fluoro(4-(1-methyl-1H- 1,2,3-triazol-4- yl)phenyl)methyl)-N-((1S,2S)-2- hydroxycyclohexyl)furo[3,2- b]pyridine-5-carboxamide(stereoisomer: retention time short)

450.2 58 7-(fluoro(4-(1-methyl-1H- 1,2,3-triazol-4- yl)phenyl)methyl)-N-((1S,2S)-2- hydroxycyclohexyl)furo[3,2- b]pyridine-5-carboxamide(stereoisomer: retention time long)

450.2 59 1,5-anhydro-2,3-dideoxy-3-(((7-(4-(1-methyl-1H-1,2,3-triazol-4- yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-D- threo-pentitol

436.2 60 1,5-anhydro-2,3-dideoxy-3-(((7- ((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

436.2 61 N-((1S,2S)-2-hydroxycyclohexyl)- 7-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,3- dihydrofuro[3,2-b]pyridine-5- carboxamide

434.1 62 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(methylcarbamoyl)benzyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

428.1 63 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(methylcarbamoyl)benzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

430.1 64 1,5-anhydro-2,3-dideoxy- 3-(((2-methyl-7-(4-(1-methyl-1H-1,2,3-triazol- 4-yl)benzyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L- threo-pentitol

448.1 65 1,5-anhydro-2,3-dideoxy- 3-(((7-(3-fluoro-4-(methylcarbamoyl)benzyl)- 2-methylfuro[3,2- b]pyridin-5-yl)carbonyl)amino)-L- threo-pentitol

442.1 66 1,5-anhydro-2,3-dideoxy- 3-(((2-methyl-7-(4-(1-methyl-1H-pyrazol-4- yl)benzyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L- threo-pentitol

447.1 67 1,5-anhydro-2,3-dideoxy- 3-(((2-methyl-7-(4-(1H- pyrazol-1-yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

433.1 68 1,5-anhydro-2,3-dideoxy- 3-(((2-methyl-7-((6-(1-methyl-1H-1,2,3-triazol- 4-yl)pyridin-3- yl)methyl)furo[3,2-b]pyridin-5- yl)carbonyl)amino)-L- threo-pentitol

449.1 69 7-(fluoro(6-(1-methyl-1H- pyrazol-4-yl)pyridin-3-yl)methyl)-N-((1S,2S)-2- hydroxycyclohexyl)furo[3,2-b]pyridine-5-carboxamide

450.1 70 7-(fluoro(6-(1-methyl-1H- pyrazol-4-yl)pyridin-3-yl)methyl)-N-((1S,2S)-2- hydroxycyclohexyl)furo[3,2-b]pyridine-5-carboxamide

450.1 71 1,5-anhydro-2,3-dideoxy-3- (((7-(4-(1-methyl-1H-1,2,3-triazol-4- yl)benzyl)furo[3,2- b]pyridin-5- yl)carbonyl)amino)-D-threo-pentitol

434.1 72 7-(3-fluoro-4- (methylcarbamoyl)benzyl)-N- ((1S,2S)-2-hydroxycyclopentyl)-2,3- dihydrofuro[3,2-b]pyridine- 5-carboxamide

414.2 73 7-(3-fluoro-4- (methylcarbamoyl)benzyl)-N- ((1S,2S)-2-hydroxycyclohexyl)-2,3- dihydrofuro[3,2-b]pyridine- 5-carboxamide

428.2 74 1,5-anhydro-2,3-dideoxy-3-(((7- (4-(1-methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol (synonym) N-((3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)-7-(4-(1-methyl-1H-imidazol- 4-yl)benzyl)-2,3-dihydrofuro[3,2-b]pyridine-5- carboxamide

435.1 75 N-(1S,2S)-2- hydroxycyclohexyl)-7-(4-(1- methyl-1H-imidazol-4-yl)benzyl)-2,3-dihydrofuro[3,2- b]pyridine-5-carboxamide

433.1 76 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)- 2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol (synonym) 7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)- N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3- dihydrofuro[3,2-b]pyridine-5- carboxamide

474.1 77 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(((2S)-tetrahydrofuran-2- ylmethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5- yl)carbonyl)amino)-L-threo- pentitol(synonym) 7-(3-fluoro-4-((((S)- tetrahydrofuran-2-yl)methyl)carbamoyl)benzyl)-N- ((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-2,3- dihydrofuro[3,2-b]pyridine-5- carboxamide

500.2 78 1,5-anhydro-3-(((7-(4- ((cyclopropylmethyl)carbamoyl)-3-fluorobenzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy- L-threo-pentitol

470.2 79 1,5-anhydro-3-(((7-(4- ((cyclopentylmethyl)carbamoyl)-3-fluorobenzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy- L-threo-pentitol

498.2 80 1,5-anhydro-3-(((7-(4- (butylcarbamoyl)-3- fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5- yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

472.2 81 1,5-anhydro-2,3-dideoxy-3-(((7- (4-(ethylcarbamoyl)-3-fluorobenzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

444.2 82 1,5-anhydro-3-(((7-(4- (cyclopropylcarbamoyl)-3-fluorobenzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy- L-threo-pentitol

456.2 83 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(isopropylcarbamoyl)benzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

458 84 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(propylcarbamoyl)benzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

458.2 85 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(isobutylcarbamoyl)benzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

472.2 86 1,5-anhydro-2,3-dideoxy-3-(((7-(4-((2-ethoxyethyl)carbamoyl)-3- fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5- yl)carbonyl)amino)-L-threo- pentitol

488.2 87 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((3-methoxypropyl)carbamoyl)benzyl)- 2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

488.2 88 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(((2R)-tetrahydrofuran-2- ylmethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5- yl)carbonyl)amino)-L-threo- pentitol

500.3 89 1,5-anhydro-3-(((7-(4-((2-tert- butoxy ethyl)carbamoyl)-3-fluorobenzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy- L-threo-pentitol

514 90 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((4-hydroxybenzyl)carbamoyl)benzyl)- 2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

522.2 91 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((3-hydroxybenzyl)carbamoyl)benzyl)- 2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

522.2 92 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((4-hydroxyphenyl)carbamoyl)benzyl)- 2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

507.9 93 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((1-methoxypropan-2-yl)carbamoyl)benzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

488.0 94 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(pentylcarbamoyl)benzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

486 95 methyl ((2-fluoro-4-((5- (((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3- dihydrofuro[3,2-b]pyridin-7-yl)methyl)benzoyl)amino)acetate

488.2 96 ((2-fluoro-4-((5-(((3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)carbamoyl)-2,3- dihydrofuro[3,2-b]pyridin-7-yl)methyl)benzoyl)amino)acetic acid

474.2 97 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((2-(isopropylsulfanyl)ethyl)- carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5- yl)carbonyl)amino)-L-threo- pentitol

518.2 98 1,5-anhydro-3-(((7-(4-((2- (tert-butylsulfanyl)ethyl)carbamoyl)- 3-fluorobenzyl)-2,3-dihydrofuro[3,2-b]pyridin-5- yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

532.4 99 1,5-anhydro-2,3-dideoxy-3-(((7- (4-((2-(diethylamino)-2-oxoethyl)carbamoyl)-3- fluorobenzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

529.2 100 1,5-anhydro-2,3-dideoxy-3-(((7- (4-((2-(dimethylamino)-2-oxoethyl)carbamoyl)-3- fluorobenzyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

501.2 101 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((2-oxo-2-(pyrrolidin-1- yl)ethyl)carbamoyl)benzyl)-2,3-dihydrofuro[3,2-b]pyridin-5- yl)carbonyl)amino)-L-threo- pentitol

527.3 102 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(((2S)-tetrahydrofuran-2- ylmethyl)carbamoyl)benzyl)- furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol (synonym) 7-(3-fluoro-4-((((S)-tetrahydrofuran-2- yl)methyl)carbamoyl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro- 2H-pyran-4-yl)furo[3,2-b]pyridine-5-carboxamide

498.2 103 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(propylcarbamoyl)benzyl)furo[3, 2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

456.2 104 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((3-methoxypropyl)carbamoyl)- benzyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

486.2 105 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-(((2R)-tetrahydrofuran-2- ylmethyl)carbamoyl)benzyl)- furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

498.2 106 1,5-anhydro-3-(((7-(4- (cyclopropylcarbamoyl)-3-fluorobenzyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

454.2 107 1,5-anhydro-2,3-dideoxy-3-(((7- (4-((2-ethoxyethyl)carbamoyl)-3-fluorobenzyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-L-threo-pentitol

486.2 108 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((tetrahydro-2H-pyran-2- ylmethyl)carbamoyl)benzyl)- furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

512.3 109 1,5-anhydro-2,3-dideoxy-3-(((7- (3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)- furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol (synonym) 7-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)- N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)furo[3,2- b]pyridine-5-carboxamide

472.2 110 1,5-anhydro-3-(((7-(4- ((cyclopropylmethyl)carbamoyl)-3-fluorobenzyl)furo[3,2- b]pyridin-5-yl)carbonyl)amino)-2,3-dideoxy-L-threo-pentitol

468.3 111 1,5-anhydro-2,3-dideoxy-3-(((7- (1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)- ethyl)furo[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

486.3 112 1,5-anhydro-2,3-dideoxy-3-(((7- (1-(3-fluoro-4-((2-methoxyethyl)carbamoyl)phenyl)- ethyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)- L-threo-pentitol

488.2 113 1,5-anhydro-2,3-dideoxy-3-(((7- ((2-methyl-1-oxo-2,3-dihydro-1H-isoindo1-5-yl)methyl)-2,3- dihydrofuro[3,2-b]pyridin-5-yl)carbonyl)amino)-L-threo- pentitol

424.2

[Table 1-21]

Formulation Example 1

(1) compound obtained in Example 1 10.0 g (2) Lactose 60.0 g (3)Cornstarch 35.0 g (4) Gelatin  3.0 g (5) Magnesium stearate  2.0 g

A mixture of the compound (10.0 g) obtained in Example 1, lactose (60.0g) and cornstarch (35.0 g) is passed through a 1 mm mesh sieve andgranulated by using 10 wt % aqueous gelatin solution (30 mL) (3.0 g asgelatin) and the granules are dried at 40° C. and sieved again. Theobtained granules are mixed with magnesium stearate (2.0 g) and themixture is compressed. The obtained core tablets are coated with a sugarcoating of an aqueous suspension of sucrose, titanium dioxide, talc andgum arabic. The coated tablets are glazed with beeswax to give 1000coated tablets.

Formulation Example 2

(1) compound obtained in Example 1 10.0 g (2) Lactose 70.0 g (3)Cornstarch 50.0 g (4) Soluble starch  7.0 g (5) Magnesium stearate  3.0g

The compound (10.0 g) obtained in Example 1 and magnesium stearate (3.0g) are granulated using aqueous soluble starch solution (70 mL) (7.0 gas soluble starch), dried and mixed with lactose (70.0 g) and cornstarch(50.0 g). The mixture is compressed to give 1000 tablets.

Experimental Example 1 Measurement of M1 Receptor Positive AllostericModulator (M1PAM) Activity

The activity of a test compound in the presence of acetylcholine at EC20concentration (final concentration 0.8-1.0 nM), which affords an actioncorresponding to about 20% of the maximum activity, was measured as PAMactivity. The method is as follows. CHO-K1 cells stably expressing ahuman M1 receptor (hCHRM1) were plated on a 384-well black clear bottomplate (BD Falcon) at 5,000 cells/well, and cultured in an incubator at37° C., 5% CO₂ for 1 day. The medium in the cell plate was removed, andassay buffer A containing calcium indicator (Recording medium (DOJINDOLABORATORIES), 0.1% BSA (Wako Pure Chemical Industries, Ltd.), 2.5 μg/mLFluo-4 AM (DOJINDO LABORATORIES), 0.08% Pluronic F127 (DOJINDOLABORATORIES), 1.25 mM probenecid (DOJINDO LABORATORIES)) was added at30 μL/well. The cells were left standing in the incubator at 37° C., 5%CO₂ for 30 min, and further left standing at room temperature for 30min. A test compound prepared by diluting with assay buffer B (HBSS(Invitrogen), 20 mM HEPES (Invitrogen), 0.1% BSA) containing 3.2-4.0 nMacetylcholine was added at 10 μL/well, and the fluorescence was measuredby FDSS/μCELL (Hamamatsu Photonics K.K.) for 1 min every for 1 second.With the definition that the amount of change in the fluorescence onaddition of acetylcholine (final concentration 1 μM) is 100% and that onaddition of DMSO instead of a test compound is 0%, the activity (%) ofthe test compound was calculated, and the inflection point in theconcentration-dependent curve of the test compound was calculated as IPvalues. The results are shown in Table 2.

TABLE 2 IP activity Example value (%) at No. (nM) 10 μM  3 13 100  8 7.9100  16 10 100  18 12  97  20 0.88  98  21 1.6 100  22 1.7 106  23 1.5 99  27 4.5 100  28 2.3 101  31 1.4 101  34 2.4 100  36 1.5  96  40 1.6 98  43 2.4 110  44 1.5 105  46 4.3 107  47 1.8 101  48 1.1 103  49 2.9104  51 0.88 104  55 0.63 107  56 42 106  57 1.1  99  60 1.6 104  61 1.8104  64 2.4 109  65 8.5 106  70 1.2  99  74 1.5 108  76 3.5 109  77 3.2108  81 5.3 108  82 6.4 110  88 7.6 111  89 25 110  90 1.4 113  96 11107  97 5.1 107 100 3.8 103 102 2.7 107 105 4.3 105 109 2.4 107 111 8.8107 113 21 109

Experimental Example 2 Rat Defecation Experiment

Male SD rats (5-6 weeks old) were used after an acclimation period forabout 1 week. A test drug (1 mg/kg or 3 mg/kg) was suspended in 0.5%methylcellulose solution and orally administered at a volume of 5 mL/kg,and the number of feces 2 hr later was counted. Only 0.5%methylcellulose was administered to a solvent administration group.

The results are shown in Table 3. The results show mean±standard error.

TABLE 3 dose solvent administra-tion Ex. group No. 0 mg/kg 1 mg/kg 3mg/kg  20 number of feces 2 hr 4.9 ± 1.0 10.6 ± 1.3  12.1 ± 1.1  later 31 number of 3.5 ± 0.6 10.0 ± 1.4  — feces 2 hr later  76 number of 3.3± 1.0 8.3 ± 0.8 10.3 ± 0.9  feces 2 hr later  77 number of 2.1 ± 0.613.9 ± 1.5  12.3 ± 1.6  feces 2 hr later 102 number of 4.4 ± 1.1 8.9 ±1.3 12.4 ± 0.9  feces 2 hr later

Experimental Example 3 Rat PK Test

As the rat, 8-week-old male SD rats (Japan SLC, Inc.) were used. Theywere fed on a solid commercially available diet (CE-2, CLEA Japan, Inc.)and allowed to freely ingest tap water as the drinking water. Anintravenous administration solution for the rats was prepared byweighing a test compound, dissolving same in dimethylacetamide (DMA)(Wako Pure Chemical Industries, Ltd.), adding the same volume of1,3-butanediol (Wako Pure Chemical Industries, Ltd.) and mixing bystirring to give a DMA:1,3-butanediol (1:1, v/v) solution. An oraladministration solution was prepared by weighing a test compound,pulverizing same in an agate mortar, and gradually adding 0.5 w/v %aqueous methylcellulose solution to give a suspension. For intravenousadministration, the solution was administered into femoral vein of therats at 0.1 mg/0.5 mL/kg (salt converted to free form). For oraladministration, the suspension was administered to the rats at 1 mg/5mL/kg (salt converted to free form). The cassette dosing method was usedfor the both administration routes, and the test compound wasadministered in the following manner.

Compound of Example 20 (intravenous: 8 compounds cassetteadministration, oral: 5 compounds cassette administration)Compound of Example 22 (intravenous: 5 compounds cassetteadministration, oral: 5 compounds cassette administration)Compound of Example 31 (intravenous: 10 compounds cassetteadministration, oral: 5 compounds cassette administration)Compound of Example 36 (intravenous: 10 compounds cassetteadministration, oral: 5 compounds cassette administration)Compound of Example 44 (intravenous: 10 compounds cassetteadministration, oral: 5 compounds cassette administration)Compound of Example 55 (intravenous: 6 compounds cassetteadministration, oral: 4 compounds cassette administration)Compound of Example 74 (intravenous: 10 compounds cassetteadministration, oral: 5 compounds cassette administration)Compound of Example 76 (intravenous: 9 compounds cassetteadministration, oral: 4 compounds cassette administration)Compound of Example 77 (intravenous: 10 compounds cassetteadministration, oral: 5 compounds cassette administration)Compound of Example 102 (intravenous: 10 compounds cassetteadministration, oral: 5 compounds cassette administration)Compound of Example 109 (intravenous: 7 compounds cassetteadministration, oral: 4 compounds cassette administration)

In the case of intravenous administration, blood samples were collectedfrom the tail vein at 5, 10, 15, 30 min, 1, 2, 4, 8 hr afteradministration, an anticoagulation treatment with heparin sodium(Shimizu Pharmaceutical Co., Ltd.) was performed, and plasma wascollected after centrifugation and subjected to the measurement of drugconcentration. In the case of oral administration, blood samples werecollected from the tail vein at 15, 30 min, 1, 2, 4, 8 hr afteradministration, an anticoagulation treatment with heparin sodium wasperformed, and plasma was collected after centrifugation and subjectedto the measurement of drug concentration.

All drug concentrations were measured by LC-MS/MS analysis. For apharmacokinetics test, the plasma (50 μL) was placed in a tube,acetonitrile (150 μL) containing internal standard solution was addedand they were mixed on a vortex mixer. Thereafter, the mixture wascentrifuged (5000 rpm, 5 min, 4° C.). The supernatant (60 μL) aftercentrifugation was added to 10 mmol/L ammonium formate (160 μL) addedearlier and mixed therewith. This sample was injected to LC/MS/MS. TheHPLC system used was Shimadzu LC-20A (Shimadzu Corporation), the columnused was Unison UK-C18 HT (3.0 μm, 2.0×20 mm, Imtakt) at 50° C., and 10mmol/L ammonium formate, 0.2% formic acid as mobile phase A andacetonitrile, 0.2% formic acid as mobile phase B were fed each at a flowrate of 1.2 mL/min under gradient conditions of (B concentration: 0min→0.1 min, 5%, 0.1→0.75 min, 5-99%, 0.75→1.15 min, 99%, 1.15→1.16 min,5%, 1.16→1.5 min, 5%). MS/MS used was AB Sciex TQ5500-MPX

(Applied Biosystems).

The results are shown in Table 4.

Tmax: time to reach maximum plasma concentrationMRT: mean residence timeiv: intravenous administrationCL total: total clearance

TABLE 4 Example Tmax MRT iv CL total No. (h) (h) (mL/h/kg)  20 2.0 1.8 246  22 2.0 1.9  280  31 1.0 1.5  200  36 1.3 1.9  327  44 1.3 1.3  286 55 1.7 0.6 1814  74 0.8 0.9  843  76 0.8 1.2  335  77 1.0 0.8  488 1021.0 0.9  703 109 1.0 1.5  404

Experimental Example 4 MDR1 Membrane Permeability Test

When MDR1 is expressed in excess in LLC-PK1 cell, which is a polar cell,MDR1 is localized in apical membrane (A), thus promoting transcellulartransport from the basement membrane side (B) toward direction A. When aratio to the transcellular transport in the opposite direction is takenand a ratio to a control cell in which a mock vector has been introducedis further taken, an efflux ratio of MDR1 to simple diffusion (correctedefflux ratio) is calculated. Similarly, when a brain/plasmaconcentration ratio in Mdr1(−/−) mouse is divided by a brain/plasmaconcentration ratio in wild-type mouse, an efflux ratio of Mdr1 tosimple diffusion in blood-brain barrier (BBB) (Kp, brain ratio, highervalue means lower central nervous system permeability) is calculated.Adachi Y. et al. (Reference 1) has reported a positive correlationbetween corrected efflux ratio and Kp, brain ratio (FIG. 5(C)), andefflux ratio in MDR1 expressing cell and Kp, brain ratio (FIG. 5(B)).That is, the report shows that a higher efflux ratio of MDR1 in vitroresults in lower central nervous system permeability.

To confirm the central nervous system permeability of the compounds ofthe present invention, a MDR1 membrane permeability test was performedby the following method.

Digoxin and lucifer yellow (LY) were purchased from Sigma-Aldrich,Diclofenac, colchicine and alprenolol were purchased from Wako PureChemical Industries, Ltd., and other reagents used were commerciallyavailable products of special grade.

Human MDR1-expressing LLC-PK1 cells were cultured according to thereport of Takeuchi et al. (Reference 2). Human MDR1-expressing LLC-PK1cells were cultured in 10% fetal bovine serum (Invitrogen), 500 μg/mlG418 (Invitrogen), 150 ng/ml colchicine-containing M199 medium(Invitrogen) under 5% CO₂ conditions at 37° C.

Transcellular transport was performed according to the report ofSugimoto et al. (Reference 3). The cells were cultured for 3 days on HTSTranswell (registered trademark) 96 well permeable support (pore size0.4 μm, 0.143 cm² surface area, Corning Life Sciences) havingpolyethylene terephthalate membrane on which the cells had been seededat 3.45×10⁴ cells/well. After preincubation in M199 medium (containing10 mmol/L HEPES, 1% BSA, pH 7.4) for 30 min, a drug solution (10 μmol/Ldigoxin, 200 μmol/L LY, 10 μmol/L test compound) dissolved in M199medium was added to the apical side or basolateral side of the Transwellby 75 or 250 μL each and the cells were cultured under 5% CO₂ conditionsat 37° C. After 1 hr, the sample was collected from the side opposite tothe side where the drug solution was added, and the concentration of thetest compound was measured by LC-MS/MS. As an internal standardsubstance, 100 ng/mL alprenolol and diclofenac were used. The analysisconditions were as follows.

LC: UFLC LC-20 (Shimadzu)

MS/MS: API4000 (AB Sciex Instruments)

LC condition: gradient method

TABLE 5 Time Pump (min) B (%) 0.02  5 0.40 95 0.80 95 0.81  5 1.50 Stop

Column: Unison UK-C18 HT (3.0 μm, 2.0×20 mm)

Column temperature: 50° C.Flow rate: 0.7 mL/min (for 1.5 min run), 1.0 mL/min (for 1.0 min run)Mobile phase A: 50 mM CH₃COONH₄:MeCN:water=1:1:8Mobile phase B: 50 mM CH₃COONH₄:MeCN=1:9Injection volume: 1-20 μL

LY was measured by a fluorescence plate reader (Fluoroskan Ascent FL).

P_(app), A to B and P_(app), B to A (apparent permeability) werecalculated from the formula (1), and the efflux ratio (ER) wascalculated from the formula (2).

$\begin{matrix}{P_{app} = \frac{Amount}{{Area} \times C_{0} \times {Time}}} & (1)\end{matrix}$

Amount: amount of transported digoxin/wellArea: surface area of cell monolayer (0.143 cm²)C₀: concentration of drug solution addedTime: incubation time

$\begin{matrix}{{ER} = \frac{P_{app},{B\mspace{14mu}{to}\mspace{14mu} A}}{P_{app},{A\mspace{14mu}{to}\mspace{14mu} B}}} & (2)\end{matrix}$

The results are shown in Table 6.

TABLE 6 MDR1 substrate screening 1 μM (MDRSUB1)/ Example Ratio No.(NUMBER)  20 4.8  22 2.6  31 11  36 9.1  44 5.5  55 6.5  74 11  76 35 77 25 102 20 109 10

REFERENCES

-   1. Adachi Y. et al., Comparative studies on in vitro methods for    evaluating in vivo function of MDR1 P-glycoprotein, Pharm. Res.    18:1660-1668, 2001-   2. Takeuchi T., Yoshitomi S., Higuchi T., Ikemoto K., Niwa S.,    Ebihara T., Katoh M., Yokoi T. and Asahi S., Establishment and    characterization of the transformants stably-expressing MDR1 derived    from various animal species in LLC-PK1, Pharm. Res.,    23(7):1460-1472, 2006-   3. Sugimoto H., Hirabayashi H., Kimura Y., Furuta A., Amano N. and    Moriwaki T., Quantitative investigation of the impact of    P-glycoprotein inhibition on drug transport across blood-brain    barrier in rats, Drug Metab. Dispos., 39(1):8-14, 2011

INDUSTRIAL APPLICABILITY

The compound of the present invention may have a cholinergic muscarinicM1 receptor positive allosteric modulator activity and may be useful asa medicament such as an agent for the prophylaxis or treatment ofconstipation and the like.

This application is based on patent application Nos. 2017-120859 and2018-005960 filed in Japan, and patent application No. 62/683,418 filedin the United States of America, the entire contents of which areincorporated by reference herein.

1. A compound represented by the formula (I):

wherein R¹ is an optionally substituted cyclic group; R² is a hydrogenatom, a halogen atom, a cyano group, an optionally substituted C₁₋₆alkyl group, or an optionally substituted C₁₋₆ alkoxy group;

is a single bond or a double bond; ring A is an optionally furthersubstituted ring; and R³ and R⁴ are each independently a hydrogen atom,a halogen atom, a hydroxy group, an optionally substituted C₁₋₆ alkylgroup, or an optionally substituted C₁₋₆ alkoxy group, or a saltthereof.
 2. The compound according to claim 1, wherein R¹ is (1) anoptionally substituted 3- to 14-membered non-aromatic heterocyclicgroup, or (2) an optionally substituted C₃₋₁₀ cycloalkyl group; R² is ahydrogen atom or an optionally substituted C₁₋₆ alkyl group; ring A is(1) an optionally further substituted benzene ring, (2) an optionallyfurther substituted 5- or 6-membered monocyclic aromatic heterocycle,(3) an optionally further substituted 4- to 6-membered monocyclicnon-aromatic heterocycle, or (4) an optionally further substituted 9- to14-membered fused polycyclic non-aromatic heterocycle; and R³ and R⁴ areeach independently a hydrogen atom, a halogen atom or an optionallysubstituted C₁₋₆ alkyl group, or a salt thereof.
 3. The compoundaccording to claim 1, wherein R¹ is (1) a 3- to 14-membered non-aromaticheterocyclic group optionally substituted by 1 to 3 hydroxy groups, or(2) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3substituents selected from a hydroxy group and a halogen atom; R² is ahydrogen atom or a C₁₋₆ alkyl group; ring A is (1) a benzene ringoptionally further substituted by 1 to 3 substituents selected from (a)a halogen atom, (b) a C₁₋₆ alkoxy group, (c) a mono- or di-C₁₋₆alkyl-carbamoyl group optionally substituted by 1 or 2 substituentsselected from (i) a C₁₋₆ alkoxy group, (ii) a C₃₋₁₀ cycloalkyl group,(iii) a 3- to 14-membered non-aromatic heterocyclic group, (iv) a C₆₋₁₄aryl group optionally substituted by 1 to 3 hydroxy groups, (v) a C₁₋₆alkoxy-carbonyl group, (vi) a carboxy group, (vii) a C₁₋₆ alkylthiogroup, (viii) a mono- or di-C₁₋₆ alkyl-carbamoyl group, and (ix) a 3- to14-membered non-aromatic heterocyclylcarbonyl group, (d) a mono- ordi-C₃₋₁₀ cycloalkyl-carbamoyl group, (e) a C₆₋₁₄ aryl-carbamoyl groupoptionally substituted by 1 to 3 hydroxy groups, and (f) a 5- to14-membered aromatic heterocyclic group optionally substituted by 1 to 3C₁₋₆ alkyl groups, (2) a 5- or 6-membered monocyclic aromaticheterocycle optionally further substituted by 1 to 3 substituentsselected from (a) a C₁₋₆ alkoxy group and (b) a 5- to 14-memberedaromatic heterocyclic group optionally substituted by 1 to 3 C₁₋₆ alkylgroups, (3) a 4- to 6-membered monocyclic non-aromatic heterocycleoptionally further substituted by one oxo group, or (4) a 9- to14-membered fused polycyclic non-aromatic heterocycle optionally furthersubstituted by 1 to 3 substituents selected from a C₁₋₆ alkyl group andan oxo group; and R³ and R⁴ are each independently a hydrogen atom, ahalogen atom or a C₁₋₆ alkyl group, or a salt thereof.
 4. The compoundaccording to claim 3, wherein R¹ is

or a salt thereof.
 5. The compound according to claim 3, wherein ring Ais (1) a benzene ring further substituted by 1 to 3 substituentsselected from (a) a halogen atom, (b) a mono- or di-C₁₋₆ alkyl-carbamoylgroup optionally substituted by 1 or 2 substituents selected from (i) aC₁₋₆ alkoxy group and (ii) a 3- to 14-membered non-aromatic heterocyclicgroup, and (c) a 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups, or (2) a 5- or6-membered monocyclic aromatic heterocycle further substituted by one 5-to 14-membered aromatic heterocyclic group optionally substituted by 1to 3 C₁₋₆ alkyl groups, or a salt thereof.
 6. The compound according toclaim 3, wherein ring A is

wherein R is a mono- or di-C₁₋₆ alkyl-carbamoyl group optionallysubstituted by 1 or 2 substituents selected from a C₁₋₆ alkoxy group anda 3- to 14-membered non-aromatic heterocyclic group; X is CR^(6A) or N;and R^(6A) is a hydrogen atom or a halogen atom, or a salt thereof. 7.The compound according to claim 3, wherein ring A is

wherein R^(5A) is a 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups; X is CR^(6A) or N;and R^(6A) is a hydrogen atom or a halogen atom, or a salt thereof. 8.The compound according to claim 1, wherein R¹ is a 3- to 14-memberednon-aromatic heterocyclic group substituted by one hydroxy group; R² isa hydrogen atom; ring A is (1) a benzene ring further substituted by 1to 3 substituents selected from (a) a halogen atom, (b) a mono- ordi-C₁₋₆ alkyl-carbamoyl group optionally substituted by 1 or 2substituents selected from (i) a C₁₋₆ alkoxy group and (ii) a 3- to14-membered non-aromatic heterocyclic group, and (c) a 5- to 14-memberedaromatic heterocyclic group optionally substituted by 1 to 3 C₁₋₆ alkylgroups, or (2) a 5- or 6-membered monocyclic aromatic heterocyclefurther substituted by one 5- to 14-membered aromatic heterocyclic groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups; and R³ and R⁴ areeach independently a hydrogen atom or a halogen atom, or a salt thereof.9. A pharmaceutical composition comprising the compound according toclaim 1 or a salt thereof and a pharmaceutically acceptable carrier. 10.The pharmaceutical composition according to claim 9, which is acholinergic muscarinic M1 receptor positive allosteric modulator. 11.The pharmaceutical composition according to claim 9, which is atherapeutic agent for constipation.
 12. A method of cholinergicmuscarinic M1 receptor positive allosteric modulation in a mammal,comprising administering an effective amount of the compound accordingto claim 1 or a salt thereof to said mammal.
 13. A method for thetreatment of constipation in a mammal, comprising administering aneffective amount of the compound according to claim 1 or a salt thereofto the mammal.